Research ArticleExperimental Studies

Effect of Chloroquine on Doxorubicin-induced Apoptosis in A549 Cells

KEISUKE SATO, NATSUKI OTA, SHOYA ENDO, AKIFUMI NAKATA, HIROSHI YAMASHITA and RYOSUKE TATSUNAMI
Anticancer Research August 2022, 42 (8) 4025-4035; DOI: https://doi.org/10.21873/anticanres.15899

Abstract

Background/Aim: We investigated the effects of chloroquine, an autophagy inhibitor, on doxorubicin-induced apoptosis in A549 cells. Materials and Methods: A549 cells were treated with doxorubicin, chloroquine, or both. Then, cytotoxicity was measured. The expression levels of caspases and mitogen-activated protein kinases were also quantified. In addition, the levels of doxorubicin-derived reactive oxygen species were measured. Results: Chloroquine enhanced doxorubicin-induced apoptosis and oxidative stress and suppressed the doxorubicin-induced extracellular-signal-regulated kinase activation. Conclusion: Chloroquine enhances doxorubicin-induced and oxidative stress-mediated apoptosis. This mechanism may involve the dephosphorylation of extracellular-signal-regulated kinases.

Key Words:

Lung cancer is a leading cause of cancer-related deaths in men and women, causing approximately 1.4 million deaths every year worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80% of all lung cancer cases (1). It is commonly treated through surgery, radiation therapy, and chemotherapy with anticancer drugs. Various types of anticancer drugs, such as cytotoxic anticancer agents and molecular-targeted drugs, are used to treat NSCLC (2).

Doxorubicin (DOX), an anthracycline anticancer drug, is widely used to treat different cancers, including NSCLC (3). However, cumulative and dose-related cardiotoxicity induced by DOX impedes its clinical use (4). DOX induces apoptosis via oxidative stress in several cancer cells (5, 6). The oxidative stress is induced by generating excessive reactive oxygen species (ROS) (7). Mitogen-activated protein kinase (MAPK) cascade is a key signaling pathway that regulates several cellular processes, including proliferation, differentiation, apoptosis, and stress response (8). The MAPK signaling pathway is also responsible for DOX-mediated toxicity (9, 10).

Autophagy is a cellular process in which aggregated proteins and damaged organelles in the cytoplasm are degraded by the lysosomes. It is a type of programmed cell death but is generally considered as a stress-responsive survival mechanism (11). It is induced under ROS-mediated oxidative stress and protects cells from apoptosis (12, 13). Autophagy is associated with many diseases such as cancer, metabolic dysfunction, neurodegenerative diseases, and inflammatory diseases (14-16). Autophagy plays a dual role in cancer development depending on the type and stage of cancer (17-19). In the early stages of cancer progression, autophagy acts as a tumor suppressor. However, once the tumors progress to advanced stages, autophagy supplies nutrients and metabolic intermediates to cancer cells under nutrient-depleted conditions to promote their survival (20, 21). This study focused on the effect of autophagy in cancer cells treated with anticancer drugs. Specifically, the study aimed to determine the effect of autophagy inhibition on DOX-induced apoptosis in NSCLC cells.

Materials and Methods

Cell culture. A549 cells were grown to 80-90% confluency in Dulbecco’s modified Eagle’s medium (DMEM; Thermo Fisher Scientific, MA, USA) containing 10% fetal bovine serum, L-glutamine (4 mM), penicillin (100 U/ml), and streptomycin (100 μg/ml) at 37°C in a humidified chamber with 5% CO2.

Cyto-ID staining. A549 cells (1×105 cells/well) were seeded in a 24-well plate and treated with DOX (Merck, Darmstadt, Germany) for 24 h, followed by staining using the Cyto-ID Autophagy Detection Kit (Enzo Life Sciences, Farmingdale, NY, USA) as per the manufacturer’s protocol. Images were captured using a confocal microscope (Carl Zeiss, Germany).

Measurement of cytotoxicity. Cell viability was measured using the Cell Titer 96AQueous One Solution Cell Proliferation Assay (MTS assay; Promega, Madison, WI, USA). Briefly, A549 cells in 96-well plates were treated with 2 μM DOX, 20 μM chloroquine (CQ, an autophagy inhibitor), or both for 4-24 h. Then, the media were discarded, cells were washed with serum-free DMEM, and incubated with complete DMEM (100 μl) and MTS assay solution (10 μl) at 37°C for 60 min. The MTS formazan produced was measured at 490 nm using a Bio-Rad Model 680 microplate reader (Hercules, CA, USA).

Cell death was assessed by measuring the lactate dehydrogenase (LDH) release. The A549 cells in 96-well plates were treated with 2 μM DOX, 20 μM CQ, or both for 4-24 h. LDH release was measured using the Cytotoxicity LDH Assay Kit-WST (DOJINDO, Kumamoto, Japan) according to the manufacturer’s protocol.

Measurement of protein levels. LC3, p62, caspase-3, cleaved caspase-3, caspase-8, cleaved caspase-8, caspase-9, cleaved caspase-9, p38 mitogen-activated protein kinase (p38), phospho-p38 (p-p38), c-Jun N-terminal kinase (JNK), phospho-JNK (p-JNK), extracellular-signal-regulated kinase (ERK), and phospho-ERK (p-ERK) protein levels were analyzed using western blotting. Briefly, cells treated with 2 μM DOX alone, 20 μM CQ, or MAPK inhibitor. Then, they were washed with Dulbecco’s phosphate-buffered saline (DPBS) and lysed in lysis buffer [50 mM HEPES (pH 7.4), 5 mM EDTA, 120 mM NaCl, 1% Triton X-100, protease inhibitors (10 μg/ml aprotinin, 1 mM phenylmethylsulfonyl fluoride, and 10 μg/ml leupeptin), and phosphatase inhibitors (50 mM sodium fluoride, 1 mM sodium orthovanadate, and 10 mM sodium pyrophosphate)]. The lysate was centrifuged at 10,000 × g for 15 min, and 20 μg protein from the supernatant was resolved using 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The separated proteins were blotted onto polyvinylidene difluoride membranes. To detect proteins, membranes were incubated with the corresponding primary antibodies: anti-rabbit caspase-3, anti-rabbit cleaved caspase-3, anti-mouse caspase-8, anti-rabbit caspase-9, anti-rabbit p38, anti-rabbit phospho-p38, anti-rabbit JNK, anti-rabbit phospho-JNK, anti-rabbit ERK, anti-rabbit phospho-ERK, anti-rabbit p62 (Cell Signaling Technology, Danvers, MA, USA), anti-rabbit LC3 polyclonal antibody (Novus Biologicals, Centennial, CO, USA), or anti-mouse β-actin polyclonal antibody (Sigma-Aldrich Co., St. Louis, MO, USA). The membranes were then incubated with horseradish peroxidase-conjugated secondary antibodies. Chemiluminescence was detected using an Immobilon block (Merck KGaA, Darmstadt, Germany).

Measurement of glutathione (GSH) levels. Intracellular GSH levels were measured using previously described spectrophotometric methods (22). A549 cells, seeded in a 12-well plate, were treated with DOX. To measure GSH levels, the samples were mixed with 0.6 mM 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB), 0.2 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), and 5 mM ethylenediaminetetraacetic acid (EDTA) in 0.1 M sodium phosphate buffer (pH 7.5). The reaction was initiated by the addition of glutathione reductase.

Measurement of ROS. Mitosox (Thermo Fisher Scientific) was used to estimate intracellular ROS. A549 cells were treated with DOX, 20 μM CQ, or both and incubated in a medium containing Mitosox for 20 min. Then, the cells were washed with DPBS. Changes in the intracellular ROS levels were visualized as red fluorescence using confocal laser scanning microscopy.

Statistical analysis. All experiments were performed independently in triplicates. Results are expressed as mean±standard deviation (SD). Statistical significance was determined using a one-way analysis of variance (ANOVA) with Tukey’s multiple comparison test. All analyses were performed using the GraphPad Prism 7 software. Differences were considered significant at p-value <0.05.

Results

DOX-induced autophagy. To measure DOX-induced autophagy, we evaluated p62 levels (a marker of autophagic activity) and autophagic flux (a measure of autophagic degradation) (23). We used LC3 as a model substrate to measure the autophagic flux. In A549 cells, DOX decreased p62 protein levels and increased autophagic flux (Figure 1A).

Figure 1.
Figure 1.

Doxorubicin (DOX)-induced autophagy. (A) Western blots of p62 and LC3 proteins detected in A549 cells treated with 2 μM DOX, 20 μM chloroquine (CQ), or both for 16 h. (B) Autophagosomes visualized under a fluorescence microscope, in A549 cells treated with 2 μM DOX for 24 h.

The Cyto-ID autophagy detection kit was used to measure autophagic activity. This kit measures the number of autophagic vacuoles and monitors autophagic flux by using a dye (Cyto-ID) that selectively labels the accumulated autophagic vacuoles. DOX increased the Cyto-ID fluorescence (Figure 1B). The results suggested that DOX induces autophagy in A549 cells.

CQ enhanced DOX-induced apoptosis. To investigate the effect of an autophagy inhibitor on DOX-induced cytotoxicity, we analyzed MTS reduction as an indicator of cell viability, and LDH release as an indicator of cell death. The combination of DOX and CQ decreased cell viability and induced cell death in A549 cells (Figure 2A and B). These results suggested that autophagy inhibitors enhance DOX-induced cytotoxicity.

Figure 2.
Figure 2.

CQ enhanced DOX-induced apoptosis. A549 cells were treated with 2 μM DOX, 20 μM CQ, or both for 24 h. Graphs depict (A) cell viability and (B) cell death as estimated by MTS assay and LDH release, respectively; (C) western blot results for expression of Caspase-3. (D) Cell viability analysis of A549 cells treated with 2 μM DOX, 20 μM CQ, or both, with or without QVD for 24 h. Values are represented as means±SD of six experiments (n=6). *Statistical significance was set at p<0.05. DOX: Doxorubicin; LDH: lactate dehydrogenase; CQ: chloroquine.

Next, we focused on apoptosis, a type of programmed cell death. We measured the levels of caspase-3 as an apoptosis indicator. Figure 2C shows that DOX slightly increased the levels of cleaved caspase-3, the activated form of caspase-3. In addition, CQ remarkably enhanced the levels of active caspase-3 in DOX-treated cells. Moreover, Quinoline-Val-Asp-Difluorophenoxymethylketone (QVD), an apoptosis inhibitor, decreased the combined cytotoxic effects of DOX and CQ. These results suggested that autophagy inhibitors enhance DOX-induced apoptosis.

Mechanism of apoptosis induced by the combination of DOX and CQ. We investigated the mechanism of apoptosis induced by the combination of DOX and CQ. Apoptosis is induced via two main routes: the mitochondrial pathway or the death receptor pathway. First, we focused on the mitochondria-mediated apoptosis that is mainly induced by oxidative stress (24). Mitosox when oxidized by superoxide, a ROS, exhibits red fluorescence. DOX increased the mitosox-derived fluorescence, and CQ further enhanced this fluorescence (Figure 3A). A549 cells treated with DOX showed a decrease in GSH (a major antioxidant) levels. CQ augmented this decrease in GSH levels (Figure 3B). These results suggested that DOX-induced oxidative stress is intensified by CQ. Caspase-9 is located downstream of the mitochondria-mediated apoptotic pathway. DOX increased the levels of cleaved caspase-9 (Figure 3C), and CQ enhanced the Dox-mediated increase in cleaved caspase-9 levels. The results suggest that CQ enhances DOX-induced mitochondrial-mediated apoptosis.

Figure 3.
Figure 3.

Mechanism of apoptosis induced by the combination of DOX and CQ. (A) Mitosox fluorescence depicting ROS production in A549 cells treated with 2 μM DOX, 20 μM CQ, or both for 24 h. (B) GSH levels in A549 cells treated with 2 μM DOX, 20 μM CQ, or both for 8 h, as estimated by DTNB recycling assay; western blot results for the expression of (C) Caspase-9, (D) Fas, and (E) Caspase-8 proteins. Values are represented as means±SD of six experiments (n=6). *Statistical significance was set at p<0.05. DOX: Doxorubicin; CQ: chloroquine; GSH: glutathione.

Next, we focused on apoptosis mediated by the death receptor (caspase-8) pathway. DOX increased Fas and cleaved caspase-8 levels (Figure 3D and E). However, CQ did not affect the DOX-induced increase in Fas and caspase-8 levels. These results suggested that CQ does not influence the DOX-induced apoptosis that is mediated by the death receptor pathway.

Effects of MAPK on DOX and CQ-induced cytotoxicity. We evaluated the expression of various members of the MAPK cascade. DOX increased phospho-p38, phospho-JNK, and phospho-ERK levels in A549 cells (Figure 4A, C and E). CQ enhanced DOX-mediated phosphorylation of p38 and JNK. In contrast, CQ inhibited DOX-mediated phosphorylation of ERK. These results suggested that autophagy inhibitors enhanced DOX-induced p38 and JNK activation and suppressed DOX-induced ERK activation.

Figure 4.
Figure 4.

Effects of MAPK on DOX and CQ-induced cytotoxicity. (A) p-p38 and p38, (C) p-JNK and JNK, and (E) p-ERK and ERK protein levels in A549 cells treated with 2 μM DOX, 20 μM CQ, or both for 24 h, as measured by western blot. (B, D, F) Cell viability of A549 cells treated with 2 μM DOX, 20 μM CQ, or both, with or without MAPK inhibitor for 24 h. Values are represented as means±SD of six experiments (n=6). *Statistical significance was set at p<0.05. DOX: Doxorubicin; CQ: chloroquine; MAPK: mitogen-activated protein kinase; JNK: c-Jun N-terminal kinase; ERK: extracellular-signal-regulated kinase.

Moreover, SB203580 (a p38 inhibitor) and SP600125 (a JNK inhibitor) did not affect DOX- and CQ-mediated decrease in cell viability. In contrast, SCH772984 (an ERK inhibitor) promoted the decrease in cell viability. These results suggested that the ERK pathway is involved in the DOX- and CQ-induced cytotoxicity.

Effect of ERK inhibitor on DOX- and CQ-induced apoptosis. Finally, we investigated the effects of SCH772984 on the cytotoxicity induced by the combination of DOX and CQ. SCH772984 enhanced ROS production in cells treated with both DOX and CQ (Figure 5A). As shown in Figure 2C and Figure 3C, it also enhanced the DOX-mediated increase in the levels of cleaved caspase-3 and cleaved caspase-9. Therefore, we investigated whether SCH772984 affects the DOX-and CQ-induced increase in the levels of cleaved caspase-3 and cleaved caspase-9 and found that SCH772984 further enhanced these levels (Figure 5B and C). These results demonstrated that SCH772984 enhances the effect of the DOX and CQ combination on mitochondria-mediated apoptosis induced by oxidative stress.

Figure 5.
Figure 5.

Effect of ERK inhibitor on DOX and CQ-induced apoptosis. (A) Mitosox fluorescence to detect ROS production; and western blots for the expression of (B) caspase-9 and (C) caspase-3 proteins in A549 cells treated with 2 μM DOX, 20 μM CQ, or both with or without the ERK inhibitor SCH772984 for 24 h. DOX: Doxorubicin; CQ: chloroquine; ERK: extracellular-signal-regulated kinase.

Discussion

The present study demonstrated that CQ, an autophagy inhibitor, enhances DOX-induced and oxidative stress-mediated apoptosis. Moreover, we found that ERK dephosphorylation was involved in this mechanism. These findings provide a more detailed understanding of the mechanisms underlying DOX-induced cytotoxicity in cancer cell lines.

NSCLC is the most common type of lung cancer. The A549 cell line used in the present study is a type of NSCLC-derived cell line. DOX, an anthracycline anticancer drug, is widely used in chemotherapy to treat various cancers, including NSCLC (3). However, various epidemiological and case reports on DOX-induced cardiotoxicity have been published (25). Although various factors, such as oxidative stress, have been reported to affect the mechanism of DOX-induced cardiotoxicity, the exact molecular mechanism has not been elucidated (26). The cardiotoxicity of DOX is dose-dependent. Therefore, safe dose limits of DOX have been established (4). The use of DOX within the defined doses is required to avoid DOX-induced cardiotoxicity.

Several reports have shown that DOX induces oxidative stress, which is a crucial factor in cardiotoxicity (27-29). Autophagy acts as a stress response mechanism to digest and remove proteins and organelles denatured by oxidative stress (30). CQ, an inhibitor of autophagy, enhanced DOX-induced oxidative stress (Figure 3A and B), supporting the findings of the previous reports. CQ also dramatically enhanced DOX-induced apoptosis (Figure 2). Besides inhibition of autophagy, other factors could also have enhanced the oxidative stress.

DOX induces apoptosis in several cell lines (5, 6, 31, 32). It activates caspase-3, -8, and -9 in HSC-2 and HL-60 cells (6). As shown in Figure 3C and E, the combination of DOX and CQ remarkably increased the cleaved caspase-9 levels compared to cleaved caspase-8 levels. These results suggested that CQ enhances DOX-induced apoptosis via the mitochondria-mediated apoptotic pathway. Moreover, CQ also augmented mitochondrial ROS production induced by DOX (Figure 3A). DOX induces mitochondrial toxicity and oxidative stress (33). One role of autophagy is to protect against oxidative stress. The p62 molecule promotes the antioxidant defense system by activating the Nrf2 pathway (34). We demonstrated that the autophagy inhibitor CQ enhances apoptosis via DOX-induced caspase-9 activation and ROS production.

As shown in Figure 4E, CQ inhibited DOX-mediated phosphorylation of ERK. Moreover, SCH772984, an ERK inhibitor, increased the DOX-and CQ-induced cytotoxicity and the levels of cleaved caspase-3 and cleaved caspase-9 (Figure 4F, and Figure 5B and C). These results suggested that ERK protects against cytotoxicity and apoptosis induced by the combination of DOX and CQ. ERK activation is widely associated with anti-apoptotic functions. ERK regulates cell proliferation and differentiation (35, 36). It can exert an anti-apoptotic effect by down-regulating and up-regulating the expression of pro-apoptotic and anti-apoptotic proteins, respectively, through both transcriptional and post-translational mechanisms (36). In contrast, several studies have reported that ERK signaling can be a pro-apoptotic pathway (37). In the present study, ERK was found to have anti-apoptotic effects that inhibited DOX- and CQ-induced apoptosis in A549 cells. Furthermore, CQ promoted the DOX-induced phosphorylation of p38 and JNK (Figure 4A and C). SB203580, a p38 inhibitor, and SP600125, a JNK inhibitor, did not affect DOX- and CQ-induced cytotoxicity (Figure 4B and D). These results indicated that compared to ERK, p38 and JNK do not contribute to DOX- and CQ-induced cytotoxicity enhancement. However, the reason behind this remains unclear and requires further investigation. Moreover, it is well known that the MAPK pathway is activated by stress responses such as oxidative stress. In the present study, we found that the inhibition of ERK activation by CQ enhanced DOX-induced oxidative stress (Figure 4E and F, and Figure 5A). This may be due to feedback inhibition of MAPK activation by oxidative stress.

Attempts to use autophagy as a therapeutic target have already been initiated. Clinical trials using CQ for cancer treatment are underway (38). In this study, we proposed a mechanism by which CQ augmented doxorubicin-induced apoptosis (Figure 6). DOX-induced autophagy protected against DOX-induced apoptosis. CQ dramatically enhanced oxidative stress-derived apoptosis potentially by inhibiting DOX-induced autophagy as well as ERK phosphorylation. These findings could contribute to the development of novel anticancer drugs in the future.

Figure 6.
Figure 6.

CQ enhances DOX-induced apoptosis via the dephosphorylation of ERK. DOX: Doxorubicin; CQ: chloroquine; ERK: extracellular-signal-regulated kinase.

Acknowledgements

The Authors would like to thank Dr. Andrew Thorburn for his helpful suggestions. This work was supported by JSPS KAKENHI (grant no. JP 20K16084).

Footnotes

  • Authors’ Contributions

    K Sato and R Tatsunami conceived and designed the experiments. K Sato, N Ota and S Endo performed the experiments and analyzed the data. A Nakata and H Yamashita analyzed and interpreted the data. K Sato and R Tatsunami wrote the manuscript. A Nakata and H Yamashita reviewed and edited the manuscript. All Authors read and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

  • Received May 20, 2022.
  • Revision received June 3, 2022.
  • Accepted June 6, 2022.

References

  1. ↵
    1. Maryam A,
    2. Mehmood T,
    3. Zhang H,
    4. Li Y,
    5. Khan M and
    6. Ma T
    : Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress. Sci Rep 7(1): 6242, 2017. PMID: 28740138. DOI: 10.1038/s41598-017-06535-y
    OpenUrlCrossRefPubMed
  2. ↵
    1. Cheng Y,
    2. Zhang T and
    3. Xu Q
    : Therapeutic advances in non-small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy. MedComm (2020) 2(4): 692-729, 2021. PMID: 34977873. DOI: 10.1002/mco2.105
    OpenUrlCrossRefPubMed
  3. ↵
    1. Minotti G,
    2. Recalcati S,
    3. Menna P,
    4. Salvatorelli E,
    5. Corna G and
    6. Cairo G
    : Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent and independent mechanisms. Methods Enzymol 378: 340-361, 2004. PMID: 15038979. DOI: 10.1016/S0076-6879(04)78025-8
    OpenUrlCrossRefPubMed
  4. ↵
    1. Minotti G,
    2. Menna P,
    3. Salvatorelli E,
    4. Cairo G and
    5. Gianni L
    : Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56(2): 185-229, 2004. PMID: 15169927. DOI: 10.1124/pr.56.2.6
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Pilco-Ferreto N and
    2. Calaf GM
    : Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines. Int J Oncol 49(2): 753-762, 2016. PMID: 27278553. DOI: 10.3892/ijo.2016.3558
    OpenUrlCrossRefPubMed
  6. ↵
    1. Suzuki F,
    2. Hashimoto K,
    3. Kikuchi H,
    4. Nishikawa H,
    5. Matsumoto H,
    6. Shimada J,
    7. Kawase M,
    8. Sunaga K,
    9. Tsuda T,
    10. Satoh K and
    11. Sakagami H
    : Induction of tumor-specific cytotoxicity and apoptosis by doxorubicin. Anticancer Res 25(2A): 887-893, 2005. PMID: 15868924.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Cappetta D,
    2. De Angelis A,
    3. Sapio L,
    4. Prezioso L,
    5. Illiano M,
    6. Quaini F,
    7. Rossi F,
    8. Berrino L,
    9. Naviglio S and
    10. Urbanek K
    : Oxidative stress and cellular response to doxorubicin: a common factor in the complex milieu of anthracycline cardiotoxicity. Oxid Med Cell Longev 2017: 1521020, 2017. PMID: 29181122. DOI: 10.1155/2017/1521020
    OpenUrlCrossRefPubMed
  8. ↵
    1. Plotnikov A,
    2. Zehorai E,
    3. Procaccia S and
    4. Seger R
    : The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813(9): 1619-1633, 2011. PMID: 21167873. DOI: 10.1016/j.bbamcr.2010.12.012
    OpenUrlCrossRefPubMed
  9. ↵
    1. Spallarossa P,
    2. Altieri P,
    3. Garibaldi S,
    4. Ghigliotti G,
    5. Barisione C,
    6. Manca V,
    7. Fabbi P,
    8. Ballestrero A,
    9. Brunelli C and
    10. Barsotti A
    : Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res 69(3): 736-745, 2006. PMID: 16213474. DOI: 10.1016/j.cardiores.2005.08.009
    OpenUrlCrossRefPubMed
  10. ↵
    1. Liu J,
    2. Mao W,
    3. Ding B and
    4. Liang CS
    : ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol Heart Circ Physiol 295(5): H1956-H1965, 2008. PMID: 18775851. DOI: 10.1152/ajpheart.00407.2008
    OpenUrlCrossRefPubMed
  11. ↵
    1. Yu L,
    2. Wan F,
    3. Dutta S,
    4. Welsh S,
    5. Liu Z,
    6. Freundt E,
    7. Baehrecke EH and
    8. Lenardo M
    : Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 103(13): 4952-4957, 2006. PMID: 16547133. DOI: 10.1073/pnas.0511288103
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Poillet-Perez L,
    2. Despouy G,
    3. Delage-Mourroux R and
    4. Boyer-Guittaut M
    : Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol 4: 184-192, 2015. PMID: 25590798. DOI: 10.1016/j.redox.2014.12.003
    OpenUrlCrossRefPubMed
  13. ↵
    1. Pan X,
    2. Zhang X,
    3. Sun H,
    4. Zhang J,
    5. Yan M and
    6. Zhang H
    : Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. PLoS One 8(2): e56679, 2013. PMID: 23441212. DOI: 10.1371/journal.pone.0056679
    OpenUrlCrossRefPubMed
  14. ↵
    1. Thorburn A
    : Autophagy and disease. J Biol Chem 293(15): 5425-5430, 2018. PMID: 29191833. DOI: 10.1074/jbc.R117.810739
    OpenUrlAbstract/FREE Full Text
    1. Condello M,
    2. Pellegrini E,
    3. Caraglia M and
    4. Meschini S
    : Targeting autophagy to overcome human diseases. Int J Mol Sci 20(3): 725, 2019. PMID: 30744021. DOI: 10.3390/ijms20030725
    OpenUrlCrossRefPubMed
  16. ↵
    1. Tsujiya Y,
    2. Yamamori M,
    3. Hasegawa AI,
    4. Yamamoto Y,
    5. Yashiro M and
    6. Okamura N
    : Telmisartan exerts cytotoxicity in scirrhous gastric cancer cells by inducing G0/G1 cell cycle arrest. Anticancer Res 41(11): 5461-5468, 2021. PMID: 34732415. DOI: 10.21873/anticanres.15358
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Eskelinen EL
    : The dual role of autophagy in cancer. Curr Opin Pharmacol 11(4): 294-300, 2011. PMID: 21498118. DOI: 10.1016/j.coph.2011.03.009
    OpenUrlCrossRefPubMed
    1. Singh SS,
    2. Vats S,
    3. Chia AY,
    4. Tan TZ,
    5. Deng S,
    6. Ong MS,
    7. Arfuso F,
    8. Yap CT,
    9. Goh BC,
    10. Sethi G,
    11. Huang RY,
    12. Shen HM,
    13. Manjithaya R and
    14. Kumar AP
    : Dual role of autophagy in hallmarks of cancer. Oncogene 37(9): 1142-1158, 2018. PMID: 29255248. DOI: 10.1038/s41388-017-0046-6
    OpenUrlCrossRefPubMed
  19. ↵
    1. Chavez-Dominguez R,
    2. Perez-Medina M,
    3. Lopez-Gonzalez JS,
    4. Galicia-Velasco M and
    5. Aguilar-Cazares D
    : The double-edge sword of autophagy in cancer: From tumor suppression to pro-tumor activity. Front Oncol 10: 578418, 2020. PMID: 33117715. DOI: 10.3389/fonc.2020.578418
    OpenUrlCrossRefPubMed
  20. ↵
    1. Barnard RA,
    2. Regan DP,
    3. Hansen RJ,
    4. Maycotte P,
    5. Thorburn A and
    6. Gustafson DL
    : Autophagy inhibition delays early but not late-stage metastatic disease. J Pharmacol Exp Ther 358(2): 282-293, 2016. PMID: 27231155. DOI: 10.1124/jpet.116.233908
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. White E
    : Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12(6): 401-410, 2012. PMID: 22534666. DOI: 10.1038/nrc3262
    OpenUrlCrossRefPubMed
  22. ↵
    1. Tsukamoto M,
    2. Tampo Y,
    3. Sawada M and
    4. Yonaha M
    : Paraquat-induced oxidative stress and dysfunction of the glutathione redox cycle in pulmonary microvascular endothelial cells. Toxicol Appl Pharmacol 178(2): 82-92, 2002. PMID: 11814328. DOI: 10.1006/taap.2001.9325
    OpenUrlCrossRefPubMed
  23. ↵
    1. Klionsky DJ,
    2. Abdalla FC,
    3. Abeliovich H,
    4. Abraham RT,
    5. Acevedo-Arozena A,
    6. Adeli K,
    7. Agholme L,
    8. Agnello M,
    9. Agostinis P,
    10. Aguirre-Ghiso JA,
    11. Ahn HJ,
    12. Ait-Mohamed O,
    13. Ait-Si-Ali S,
    14. Akematsu T,
    15. Akira S,
    16. Al-Younes HM,
    17. Al-Zeer MA,
    18. Albert ML,
    19. Albin RL,
    20. Alegre-Abarrategui J,
    21. Aleo MF,
    22. Alirezaei M,
    23. Almasan A,
    24. Almonte-Becerril M,
    25. Amano A,
    26. Amaravadi R,
    27. Amarnath S,
    28. Amer AO,
    29. Andrieu-Abadie N,
    30. Anantharam V,
    31. Ann DK,
    32. Anoopkumar-Dukie S,
    33. Aoki H,
    34. Apostolova N,
    35. Arancia G,
    36. Aris JP,
    37. Asanuma K,
    38. Asare NY,
    39. Ashida H,
    40. Askanas V,
    41. Askew DS,
    42. Auberger P,
    43. Baba M,
    44. Backues SK,
    45. Baehrecke EH,
    46. Bahr BA,
    47. Bai XY,
    48. Bailly Y,
    49. Baiocchi R,
    50. Baldini G,
    51. Balduini W,
    52. Ballabio A,
    53. Bamber BA,
    54. Bampton ET,
    55. Bánhegyi G,
    56. Bartholomew CR,
    57. Bassham DC,
    58. Bast RC Jr.,
    59. Batoko H,
    60. Bay BH,
    61. Beau I,
    62. Béchet DM,
    63. Begley TJ,
    64. Behl C,
    65. Behrends C,
    66. Bekri S,
    67. Bellaire B,
    68. Bendall LJ,
    69. Benetti L,
    70. Berliocchi L,
    71. Bernardi H,
    72. Bernassola F,
    73. Besteiro S,
    74. Bhatia-Kissova I,
    75. Bi X,
    76. Biard-Piechaczyk M,
    77. Blum JS,
    78. Boise LH,
    79. Bonaldo P,
    80. Boone DL,
    81. Bornhauser BC,
    82. Bortoluci KR,
    83. Bossis I,
    84. Bost F,
    85. Bourquin JP,
    86. Boya P,
    87. Boyer-Guittaut M,
    88. Bozhkov PV,
    89. Brady NR,
    90. Brancolini C,
    91. Brech A,
    92. Brenman JE,
    93. Brennand A,
    94. Bresnick EH,
    95. Brest P,
    96. Bridges D,
    97. Bristol ML,
    98. Brookes PS,
    99. Brown EJ,
    100. Brumell JH,
    101. Brunetti-Pierri N,
    102. Brunk UT,
    103. Bulman DE,
    104. Bultman SJ,
    105. Bultynck G,
    106. Burbulla LF,
    107. Bursch W,
    108. Butchar JP,
    109. Buzgariu W,
    110. Bydlowski SP,
    111. Cadwell K,
    112. Cahová M,
    113. Cai D,
    114. Cai J,
    115. Cai Q,
    116. Calabretta B,
    117. Calvo-Garrido J,
    118. Camougrand N,
    119. Campanella M,
    120. Campos-Salinas J,
    121. Candi E,
    122. Cao L,
    123. Caplan AB,
    124. Carding SR,
    125. Cardoso SM,
    126. Carew JS,
    127. Carlin CR,
    128. Carmignac V,
    129. Carneiro LA,
    130. Carra S,
    131. Caruso RA,
    132. Casari G,
    133. Casas C,
    134. Castino R,
    135. Cebollero E,
    136. Cecconi F,
    137. Celli J,
    138. Chaachouay H,
    139. Chae HJ,
    140. Chai CY,
    141. Chan DC,
    142. Chan EY,
    143. Chang RC,
    144. Che CM,
    145. Chen CC,
    146. Chen GC,
    147. Chen GQ,
    148. Chen M,
    149. Chen Q,
    150. Chen SS,
    151. Chen W,
    152. Chen X,
    153. Chen X,
    154. Chen X,
    155. Chen YG,
    156. Chen Y,
    157. Chen Y,
    158. Chen YJ,
    159. Chen Z,
    160. Cheng A,
    161. Cheng CH,
    162. Cheng Y,
    163. Cheong H,
    164. Cheong JH,
    165. Cherry S,
    166. Chess-Williams R,
    167. Cheung ZH,
    168. Chevet E,
    169. Chiang HL,
    170. Chiarelli R,
    171. Chiba T,
    172. Chin LS,
    173. Chiou SH,
    174. Chisari FV,
    175. Cho CH,
    176. Cho DH,
    177. Choi AM,
    178. Choi D,
    179. Choi KS,
    180. Choi ME,
    181. Chouaib S,
    182. Choubey D,
    183. Choubey V,
    184. Chu CT,
    185. Chuang TH,
    186. Chueh SH,
    187. Chun T,
    188. Chwae YJ,
    189. Chye ML,
    190. Ciarcia R,
    191. Ciriolo MR,
    192. Clague MJ,
    193. Clark RS,
    194. Clarke PG,
    195. Clarke R,
    196. Codogno P,
    197. Coller HA,
    198. Colombo MI,
    199. Comincini S,
    200. Condello M,
    201. Condorelli F,
    202. Cookson MR,
    203. Coombs GH,
    204. Coppens I,
    205. Corbalan R,
    206. Cossart P,
    207. Costelli P,
    208. Costes S,
    209. Coto-Montes A,
    210. Couve E,
    211. Coxon FP,
    212. Cregg JM,
    213. Crespo JL,
    214. Cronjé MJ,
    215. Cuervo AM,
    216. Cullen JJ,
    217. Czaja MJ,
    218. D’Amelio M,
    219. Darfeuille-Michaud A,
    220. Davids LM,
    221. Davies FE,
    222. De Felici M,
    223. de Groot JF,
    224. de Haan CA,
    225. De Martino L,
    226. De Milito A,
    227. De Tata V,
    228. Debnath J,
    229. Degterev A,
    230. Dehay B,
    231. Delbridge LM,
    232. Demarchi F,
    233. Deng YZ,
    234. Dengjel J,
    235. Dent P,
    236. Denton D,
    237. Deretic V,
    238. Desai SD,
    239. Devenish RJ,
    240. Di Gioacchino M,
    241. Di Paolo G,
    242. Di Pietro C,
    243. Díaz-Araya G,
    244. Díaz-Laviada I,
    245. Diaz-Meco MT,
    246. Diaz-Nido J,
    247. Dikic I,
    248. Dinesh-Kumar SP,
    249. Ding WX,
    250. Distelhorst CW,
    251. Diwan A,
    252. Djavaheri-Mergny M,
    253. Dokudovskaya S,
    254. Dong Z,
    255. Dorsey FC,
    256. Dosenko V,
    257. Dowling JJ,
    258. Doxsey S,
    259. Dreux M,
    260. Drew ME,
    261. Duan Q,
    262. Duchosal MA,
    263. Duff K,
    264. Dugail I,
    265. Durbeej M,
    266. Duszenko M,
    267. Edelstein CL,
    268. Edinger AL,
    269. Egea G,
    270. Eichinger L,
    271. Eissa NT,
    272. Ekmekcioglu S,
    273. El-Deiry WS,
    274. Elazar Z,
    275. Elgendy M,
    276. Ellerby LM,
    277. Eng KE,
    278. Engelbrecht AM,
    279. Engelender S,
    280. Erenpreisa J,
    281. Escalante R,
    282. Esclatine A,
    283. Eskelinen EL,
    284. Espert L,
    285. Espina V,
    286. Fan H,
    287. Fan J,
    288. Fan QW,
    289. Fan Z,
    290. Fang S,
    291. Fang Y,
    292. Fanto M,
    293. Fanzani A,
    294. Farkas T,
    295. Farré JC,
    296. Faure M,
    297. Fechheimer M,
    298. Feng CG,
    299. Feng J,
    300. Feng Q,
    301. Feng Y,
    302. Fésüs L,
    303. Feuer R,
    304. Figueiredo-Pereira ME,
    305. Fimia GM,
    306. Fingar DC,
    307. Finkbeiner S,
    308. Finkel T,
    309. Finley KD,
    310. Fiorito F,
    311. Fisher EA,
    312. Fisher PB,
    313. Flajolet M,
    314. Florez-McClure ML,
    315. Florio S,
    316. Fon EA,
    317. Fornai F,
    318. Fortunato F,
    319. Fotedar R,
    320. Fowler DH,
    321. Fox HS,
    322. Franco R,
    323. Frankel LB,
    324. Fransen M,
    325. Fuentes JM,
    326. Fueyo J,
    327. Fujii J,
    328. Fujisaki K,
    329. Fujita E,
    330. Fukuda M,
    331. Furukawa RH,
    332. Gaestel M,
    333. Gailly P,
    334. Gajewska M,
    335. Galliot B,
    336. Galy V,
    337. Ganesh S,
    338. Ganetzky B,
    339. Ganley IG,
    340. Gao FB,
    341. Gao GF,
    342. Gao J,
    343. Garcia L,
    344. Garcia-Manero G,
    345. Garcia-Marcos M,
    346. Garmyn M,
    347. Gartel AL,
    348. Gatti E,
    349. Gautel M,
    350. Gawriluk TR,
    351. Gegg ME,
    352. Geng J,
    353. Germain M,
    354. Gestwicki JE,
    355. Gewirtz DA,
    356. Ghavami S,
    357. Ghosh P,
    358. Giammarioli AM,
    359. Giatromanolaki AN,
    360. Gibson SB,
    361. Gilkerson RW,
    362. Ginger ML,
    363. Ginsberg HN,
    364. Golab J,
    365. Goligorsky MS,
    366. Golstein P,
    367. Gomez-Manzano C,
    368. Goncu E,
    369. Gongora C,
    370. Gonzalez CD,
    371. Gonzalez R,
    372. González-Estévez C,
    373. González-Polo RA,
    374. Gonzalez-Rey E,
    375. Gorbunov NV,
    376. Gorski S,
    377. Goruppi S,
    378. Gottlieb RA,
    379. Gozuacik D,
    380. Granato GE,
    381. Grant GD,
    382. Green KN,
    383. Gregorc A,
    384. Gros F,
    385. Grose C,
    386. Grunt TW,
    387. Gual P,
    388. Guan JL,
    389. Guan KL,
    390. Guichard SM,
    391. Gukovskaya AS,
    392. Gukovsky I,
    393. Gunst J,
    394. Gustafsson AB,
    395. Halayko AJ,
    396. Hale AN,
    397. Halonen SK,
    398. Hamasaki M,
    399. Han F,
    400. Han T,
    401. Hancock MK,
    402. Hansen M,
    403. Harada H,
    404. Harada M,
    405. Hardt SE,
    406. Harper JW,
    407. Harris AL,
    408. Harris J,
    409. Harris SD,
    410. Hashimoto M,
    411. Haspel JA,
    412. Hayashi S,
    413. Hazelhurst LA,
    414. He C,
    415. He YW,
    416. Hébert MJ,
    417. Heidenreich KA,
    418. Helfrich MH,
    419. Helgason GV,
    420. Henske EP,
    421. Herman B,
    422. Herman PK,
    423. Hetz C,
    424. Hilfiker S,
    425. Hill JA,
    426. Hocking LJ,
    427. Hofman P,
    428. Hofmann TG,
    429. Höhfeld J,
    430. Holyoake TL,
    431. Hong MH,
    432. Hood DA,
    433. Hotamisligil GS,
    434. Houwerzijl EJ,
    435. Høyer-Hansen M,
    436. Hu B,
    437. Hu CA,
    438. Hu HM,
    439. Hua Y,
    440. Huang C,
    441. Huang J,
    442. Huang S,
    443. Huang WP,
    444. Huber TB,
    445. Huh WK,
    446. Hung TH,
    447. Hupp TR,
    448. Hur GM,
    449. Hurley JB,
    450. Hussain SN,
    451. Hussey PJ,
    452. Hwang JJ,
    453. Hwang S,
    454. Ichihara A,
    455. Ilkhanizadeh S,
    456. Inoki K,
    457. Into T,
    458. Iovane V,
    459. Iovanna JL,
    460. Ip NY,
    461. Isaka Y,
    462. Ishida H,
    463. Isidoro C,
    464. Isobe K,
    465. Iwasaki A,
    466. Izquierdo M,
    467. Izumi Y,
    468. Jaakkola PM,
    469. Jäättelä M,
    470. Jackson GR,
    471. Jackson WT,
    472. Janji B,
    473. Jendrach M,
    474. Jeon JH,
    475. Jeung EB,
    476. Jiang H,
    477. Jiang H,
    478. Jiang JX,
    479. Jiang M,
    480. Jiang Q,
    481. Jiang X,
    482. Jiang X,
    483. Jiménez A,
    484. Jin M,
    485. Jin S,
    486. Joe CO,
    487. Johansen T,
    488. Johnson DE,
    489. Johnson GV,
    490. Jones NL,
    491. Joseph B,
    492. Joseph SK,
    493. Joubert AM,
    494. Juhász G,
    495. Juillerat-Jeanneret L,
    496. Jung CH,
    497. Jung YK,
    498. Kaarniranta K,
    499. Kaasik A,
    500. Kabuta T,
    501. Kadowaki M,
    502. Kagedal K,
    503. Kamada Y,
    504. Kaminskyy VO,
    505. Kampinga HH,
    506. Kanamori H,
    507. Kang C,
    508. Kang KB,
    509. Kang KI,
    510. Kang R,
    511. Kang YA,
    512. Kanki T,
    513. Kanneganti TD,
    514. Kanno H,
    515. Kanthasamy AG,
    516. Kanthasamy A,
    517. Karantza V,
    518. Kaushal GP,
    519. Kaushik S,
    520. Kawazoe Y,
    521. Ke PY,
    522. Kehrl JH,
    523. Kelekar A,
    524. Kerkhoff C,
    525. Kessel DH,
    526. Khalil H,
    527. Kiel JA,
    528. Kiger AA,
    529. Kihara A,
    530. Kim DR,
    531. Kim DH,
    532. Kim DH,
    533. Kim EK,
    534. Kim HR,
    535. Kim JS,
    536. Kim JH,
    537. Kim JC,
    538. Kim JK,
    539. Kim PK,
    540. Kim SW,
    541. Kim YS,
    542. Kim Y,
    543. Kimchi A,
    544. Kimmelman AC,
    545. King JS,
    546. Kinsella TJ,
    547. Kirkin V,
    548. Kirshenbaum LA,
    549. Kitamoto K,
    550. Kitazato K,
    551. Klein L,
    552. Klimecki WT,
    553. Klucken J,
    554. Knecht E,
    555. Ko BC,
    556. Koch JC,
    557. Koga H,
    558. Koh JY,
    559. Koh YH,
    560. Koike M,
    561. Komatsu M,
    562. Kominami E,
    563. Kong HJ,
    564. Kong WJ,
    565. Korolchuk VI,
    566. Kotake Y,
    567. Koukourakis MI,
    568. Kouri Flores JB,
    569. Kovács AL,
    570. Kraft C,
    571. Krainc D,
    572. Krämer H,
    573. Kretz-Remy C,
    574. Krichevsky AM,
    575. Kroemer G,
    576. Krüger R,
    577. Krut O,
    578. Ktistakis NT,
    579. Kuan CY,
    580. Kucharczyk R,
    581. Kumar A,
    582. Kumar R,
    583. Kumar S,
    584. Kundu M,
    585. Kung HJ,
    586. Kurz T,
    587. Kwon HJ,
    588. La Spada AR,
    589. Lafont F,
    590. Lamark T,
    591. Landry J,
    592. Lane JD,
    593. Lapaquette P,
    594. Laporte JF,
    595. László L,
    596. Lavandero S,
    597. Lavoie JN,
    598. Layfield R,
    599. Lazo PA,
    600. Le W,
    601. Le Cam L,
    602. Ledbetter DJ,
    603. Lee AJ,
    604. Lee BW,
    605. Lee GM,
    606. Lee J,
    607. Lee JH,
    608. Lee M,
    609. Lee MS,
    610. Lee SH,
    611. Leeuwenburgh C,
    612. Legembre P,
    613. Legouis R,
    614. Lehmann M,
    615. Lei HY,
    616. Lei QY,
    617. Leib DA,
    618. Leiro J,
    619. Lemasters JJ,
    620. Lemoine A,
    621. Lesniak MS,
    622. Lev D,
    623. Levenson VV,
    624. Levine B,
    625. Levy E,
    626. Li F,
    627. Li JL,
    628. Li L,
    629. Li S,
    630. Li W,
    631. Li XJ,
    632. Li YB,
    633. Li YP,
    634. Liang C,
    635. Liang Q,
    636. Liao YF,
    637. Liberski PP,
    638. Lieberman A,
    639. Lim HJ,
    640. Lim KL,
    641. Lim K,
    642. Lin CF,
    643. Lin FC,
    644. Lin J,
    645. Lin JD,
    646. Lin K,
    647. Lin WW,
    648. Lin WC,
    649. Lin YL,
    650. Linden R,
    651. Lingor P,
    652. Lippincott-Schwartz J,
    653. Lisanti MP,
    654. Liton PB,
    655. Liu B,
    656. Liu CF,
    657. Liu K,
    658. Liu L,
    659. Liu QA,
    660. Liu W,
    661. Liu YC,
    662. Liu Y,
    663. Lockshin RA,
    664. Lok CN,
    665. Lonial S,
    666. Loos B,
    667. Lopez-Berestein G,
    668. López-Otín C,
    669. Lossi L,
    670. Lotze MT,
    671. Lőw P,
    672. Lu B,
    673. Lu B,
    674. Lu B,
    675. Lu Z,
    676. Luciano F,
    677. Lukacs NW,
    678. Lund AH,
    679. Lynch-Day MA,
    680. Ma Y,
    681. Macian F,
    682. MacKeigan JP,
    683. Macleod KF,
    684. Madeo F,
    685. Maiuri L,
    686. Maiuri MC,
    687. Malagoli D,
    688. Malicdan MC,
    689. Malorni W,
    690. Man N,
    691. Mandelkow EM,
    692. Manon S,
    693. Manov I,
    694. Mao K,
    695. Mao X,
    696. Mao Z,
    697. Marambaud P,
    698. Marazziti D,
    699. Marcel YL,
    700. Marchbank K,
    701. Marchetti P,
    702. Marciniak SJ,
    703. Marcondes M,
    704. Mardi M,
    705. Marfe G,
    706. Mariño G,
    707. Markaki M,
    708. Marten MR,
    709. Martin SJ,
    710. Martinand-Mari C,
    711. Martinet W,
    712. Martinez-Vicente M,
    713. Masini M,
    714. Matarrese P,
    715. Matsuo S,
    716. Matteoni R,
    717. Mayer A,
    718. Mazure NM,
    719. McConkey DJ,
    720. McConnell MJ,
    721. McDermott C,
    722. McDonald C,
    723. McInerney GM,
    724. McKenna SL,
    725. McLaughlin B,
    726. McLean PJ,
    727. McMaster CR,
    728. McQuibban GA,
    729. Meijer AJ,
    730. Meisler MH,
    731. Meléndez A,
    732. Melia TJ,
    733. Melino G,
    734. Mena MA,
    735. Menendez JA,
    736. Menna-Barreto RF,
    737. Menon MB,
    738. Menzies FM,
    739. Mercer CA,
    740. Merighi A,
    741. Merry DE,
    742. Meschini S,
    743. Meyer CG,
    744. Meyer TF,
    745. Miao CY,
    746. Miao JY,
    747. Michels PA,
    748. Michiels C,
    749. Mijaljica D,
    750. Milojkovic A,
    751. Minucci S,
    752. Miracco C,
    753. Miranti CK,
    754. Mitroulis I,
    755. Miyazawa K,
    756. Mizushima N,
    757. Mograbi B,
    758. Mohseni S,
    759. Molero X,
    760. Mollereau B,
    761. Mollinedo F,
    762. Momoi T,
    763. Monastyrska I,
    764. Monick MM,
    765. Monteiro MJ,
    766. Moore MN,
    767. Mora R,
    768. Moreau K,
    769. Moreira PI,
    770. Moriyasu Y,
    771. Moscat J,
    772. Mostowy S,
    773. Mottram JC,
    774. Motyl T,
    775. Moussa CE,
    776. Müller S,
    777. Muller S,
    778. Münger K,
    779. Münz C,
    780. Murphy LO,
    781. Murphy ME,
    782. Musarò A,
    783. Mysorekar I,
    784. Nagata E,
    785. Nagata K,
    786. Nahimana A,
    787. Nair U,
    788. Nakagawa T,
    789. Nakahira K,
    790. Nakano H,
    791. Nakatogawa H,
    792. Nanjundan M,
    793. Naqvi NI,
    794. Narendra DP,
    795. Narita M,
    796. Navarro M,
    797. Nawrocki ST,
    798. Nazarko TY,
    799. Nemchenko A,
    800. Netea MG,
    801. Neufeld TP,
    802. Ney PA,
    803. Nezis IP,
    804. Nguyen HP,
    805. Nie D,
    806. Nishino I,
    807. Nislow C,
    808. Nixon RA,
    809. Noda T,
    810. Noegel AA,
    811. Nogalska A,
    812. Noguchi S,
    813. Notterpek L,
    814. Novak I,
    815. Nozaki T,
    816. Nukina N,
    817. Nürnberger T,
    818. Nyfeler B,
    819. Obara K,
    820. Oberley TD,
    821. Oddo S,
    822. Ogawa M,
    823. Ohashi T,
    824. Okamoto K,
    825. Oleinick NL,
    826. Oliver FJ,
    827. Olsen LJ,
    828. Olsson S,
    829. Opota O,
    830. Osborne TF,
    831. Ostrander GK,
    832. Otsu K,
    833. Ou JH,
    834. Ouimet M,
    835. Overholtzer M,
    836. Ozpolat B,
    837. Paganetti P,
    838. Pagnini U,
    839. Pallet N,
    840. Palmer GE,
    841. Palumbo C,
    842. Pan T,
    843. Panaretakis T,
    844. Pandey UB,
    845. Papackova Z,
    846. Papassideri I,
    847. Paris I,
    848. Park J,
    849. Park OK,
    850. Parys JB,
    851. Parzych KR,
    852. Patschan S,
    853. Patterson C,
    854. Pattingre S,
    855. Pawelek JM,
    856. Peng J,
    857. Perlmutter DH,
    858. Perrotta I,
    859. Perry G,
    860. Pervaiz S,
    861. Peter M,
    862. Peters GJ,
    863. Petersen M,
    864. Petrovski G,
    865. Phang JM,
    866. Piacentini M,
    867. Pierre P,
    868. Pierrefite-Carle V,
    869. Pierron G,
    870. Pinkas-Kramarski R,
    871. Piras A,
    872. Piri N,
    873. Platanias LC,
    874. Pöggeler S,
    875. Poirot M,
    876. Poletti A,
    877. Poüs C,
    878. Pozuelo-Rubio M,
    879. Prætorius-Ibba M,
    880. Prasad A,
    881. Prescott M,
    882. Priault M,
    883. Produit-Zengaffinen N,
    884. Progulske-Fox A,
    885. Proikas-Cezanne T,
    886. Przedborski S,
    887. Przyklenk K,
    888. Puertollano R,
    889. Puyal J,
    890. Qian SB,
    891. Qin L,
    892. Qin ZH,
    893. Quaggin SE,
    894. Raben N,
    895. Rabinowich H,
    896. Rabkin SW,
    897. Rahman I,
    898. Rami A,
    899. Ramm G,
    900. Randall G,
    901. Randow F,
    902. Rao VA,
    903. Rathmell JC,
    904. Ravikumar B,
    905. Ray SK,
    906. Reed BH,
    907. Reed JC,
    908. Reggiori F,
    909. Régnier-Vigouroux A,
    910. Reichert AS,
    911. Reiners JJ Jr.,
    912. Reiter RJ,
    913. Ren J,
    914. Revuelta JL,
    915. Rhodes CJ,
    916. Ritis K,
    917. Rizzo E,
    918. Robbins J,
    919. Roberge M,
    920. Roca H,
    921. Roccheri MC,
    922. Rocchi S,
    923. Rodemann HP,
    924. Rodríguez de Córdoba S,
    925. Rohrer B,
    926. Roninson IB,
    927. Rosen K,
    928. Rost-Roszkowska MM,
    929. Rouis M,
    930. Rouschop KM,
    931. Rovetta F,
    932. Rubin BP,
    933. Rubinsztein DC,
    934. Ruckdeschel K,
    935. Rucker EB 3rd.,
    936. Rudich A,
    937. Rudolf E,
    938. Ruiz-Opazo N,
    939. Russo R,
    940. Rusten TE,
    941. Ryan KM,
    942. Ryter SW,
    943. Sabatini DM,
    944. Sadoshima J,
    945. Saha T,
    946. Saitoh T,
    947. Sakagami H,
    948. Sakai Y,
    949. Salekdeh GH,
    950. Salomoni P,
    951. Salvaterra PM,
    952. Salvesen G,
    953. Salvioli R,
    954. Sanchez AM,
    955. Sánchez-Alcázar JA,
    956. Sánchez-Prieto R,
    957. Sandri M,
    958. Sankar U,
    959. Sansanwal P,
    960. Santambrogio L,
    961. Saran S,
    962. Sarkar S,
    963. Sarwal M,
    964. Sasakawa C,
    965. Sasnauskiene A,
    966. Sass M,
    967. Sato K,
    968. Sato M,
    969. Schapira AH,
    970. Scharl M,
    971. Schätzl HM,
    972. Scheper W,
    973. Schiaffino S,
    974. Schneider C,
    975. Schneider ME,
    976. Schneider-Stock R,
    977. Schoenlein PV,
    978. Schorderet DF,
    979. Schüller C,
    980. Schwartz GK,
    981. Scorrano L,
    982. Sealy L,
    983. Seglen PO,
    984. Segura-Aguilar J,
    985. Seiliez I,
    986. Seleverstov O,
    987. Sell C,
    988. Seo JB,
    989. Separovic D,
    990. Setaluri V,
    991. Setoguchi T,
    992. Settembre C,
    993. Shacka JJ,
    994. Shanmugam M,
    995. Shapiro IM,
    996. Shaulian E,
    997. Shaw RJ,
    998. Shelhamer JH,
    999. Shen HM,
    1000. Shen WC,
    1001. Sheng ZH,
    1002. Shi Y,
    1003. Shibuya K,
    1004. Shidoji Y,
    1005. Shieh JJ,
    1006. Shih CM,
    1007. Shimada Y,
    1008. Shimizu S,
    1009. Shintani T,
    1010. Shirihai OS,
    1011. Shore GC,
    1012. Sibirny AA,
    1013. Sidhu SB,
    1014. Sikorska B,
    1015. Silva-Zacarin EC,
    1016. Simmons A,
    1017. Simon AK,
    1018. Simon HU,
    1019. Simone C,
    1020. Simonsen A,
    1021. Sinclair DA,
    1022. Singh R,
    1023. Sinha D,
    1024. Sinicrope FA,
    1025. Sirko A,
    1026. Siu PM,
    1027. Sivridis E,
    1028. Skop V,
    1029. Skulachev VP,
    1030. Slack RS,
    1031. Smaili SS,
    1032. Smith DR,
    1033. Soengas MS,
    1034. Soldati T,
    1035. Song X,
    1036. Sood AK,
    1037. Soong TW,
    1038. Sotgia F,
    1039. Spector SA,
    1040. Spies CD,
    1041. Springer W,
    1042. Srinivasula SM,
    1043. Stefanis L,
    1044. Steffan JS,
    1045. Stendel R,
    1046. Stenmark H,
    1047. Stephanou A,
    1048. Stern ST,
    1049. Sternberg C,
    1050. Stork B,
    1051. Strålfors P,
    1052. Subauste CS,
    1053. Sui X,
    1054. Sulzer D,
    1055. Sun J,
    1056. Sun SY,
    1057. Sun ZJ,
    1058. Sung JJ,
    1059. Suzuki K,
    1060. Suzuki T,
    1061. Swanson MS,
    1062. Swanton C,
    1063. Sweeney ST,
    1064. Sy LK,
    1065. Szabadkai G,
    1066. Tabas I,
    1067. Taegtmeyer H,
    1068. Tafani M,
    1069. Takács-Vellai K,
    1070. Takano Y,
    1071. Takegawa K,
    1072. Takemura G,
    1073. Takeshita F,
    1074. Talbot NJ,
    1075. Tan KS,
    1076. Tanaka K,
    1077. Tanaka K,
    1078. Tang D,
    1079. Tang D,
    1080. Tanida I,
    1081. Tannous BA,
    1082. Tavernarakis N,
    1083. Taylor GS,
    1084. Taylor GA,
    1085. Taylor JP,
    1086. Terada LS,
    1087. Terman A,
    1088. Tettamanti G,
    1089. Thevissen K,
    1090. Thompson CB,
    1091. Thorburn A,
    1092. Thumm M,
    1093. Tian F,
    1094. Tian Y,
    1095. Tocchini-Valentini G,
    1096. Tolkovsky AM,
    1097. Tomino Y,
    1098. Tönges L,
    1099. Tooze SA,
    1100. Tournier C,
    1101. Tower J,
    1102. Towns R,
    1103. Trajkovic V,
    1104. Travassos LH,
    1105. Tsai TF,
    1106. Tschan MP,
    1107. Tsubata T,
    1108. Tsung A,
    1109. Turk B,
    1110. Turner LS,
    1111. Tyagi SC,
    1112. Uchiyama Y,
    1113. Ueno T,
    1114. Umekawa M,
    1115. Umemiya-Shirafuji R,
    1116. Unni VK,
    1117. Vaccaro MI,
    1118. Valente EM,
    1119. Van den Berghe G,
    1120. van der Klei IJ,
    1121. van Doorn W,
    1122. van Dyk LF,
    1123. van Egmond M,
    1124. van Grunsven LA,
    1125. Vandenabeele P,
    1126. Vandenberghe WP,
    1127. Vanhorebeek I,
    1128. Vaquero EC,
    1129. Velasco G,
    1130. Vellai T,
    1131. Vicencio JM,
    1132. Vierstra RD,
    1133. Vila M,
    1134. Vindis C,
    1135. Viola G,
    1136. Viscomi MT,
    1137. Voitsekhovskaja OV,
    1138. von Haefen C,
    1139. Votruba M,
    1140. Wada K,
    1141. Wade-Martins R,
    1142. Walker CL,
    1143. Walsh CM,
    1144. Walter J,
    1145. Wan XB,
    1146. Wang A,
    1147. Wang C,
    1148. Wang D,
    1149. Wang F,
    1150. Wang F,
    1151. Wang G,
    1152. Wang H,
    1153. Wang HG,
    1154. Wang HD,
    1155. Wang J,
    1156. Wang K,
    1157. Wang M,
    1158. Wang RC,
    1159. Wang X,
    1160. Wang X,
    1161. Wang YJ,
    1162. Wang Y,
    1163. Wang Z,
    1164. Wang ZC,
    1165. Wang Z,
    1166. Wansink DG,
    1167. Ward DM,
    1168. Watada H,
    1169. Waters SL,
    1170. Webster P,
    1171. Wei L,
    1172. Weihl CC,
    1173. Weiss WA,
    1174. Welford SM,
    1175. Wen LP,
    1176. Whitehouse CA,
    1177. Whitton JL,
    1178. Whitworth AJ,
    1179. Wileman T,
    1180. Wiley JW,
    1181. Wilkinson S,
    1182. Willbold D,
    1183. Williams RL,
    1184. Williamson PR,
    1185. Wouters BG,
    1186. Wu C,
    1187. Wu DC,
    1188. Wu WK,
    1189. Wyttenbach A,
    1190. Xavier RJ,
    1191. Xi Z,
    1192. Xia P,
    1193. Xiao G,
    1194. Xie Z,
    1195. Xie Z,
    1196. Xu DZ,
    1197. Xu J,
    1198. Xu L,
    1199. Xu X,
    1200. Yamamoto A,
    1201. Yamamoto A,
    1202. Yamashina S,
    1203. Yamashita M,
    1204. Yan X,
    1205. Yanagida M,
    1206. Yang DS,
    1207. Yang E,
    1208. Yang JM,
    1209. Yang SY,
    1210. Yang W,
    1211. Yang WY,
    1212. Yang Z,
    1213. Yao MC,
    1214. Yao TP,
    1215. Yeganeh B,
    1216. Yen WL,
    1217. Yin JJ,
    1218. Yin XM,
    1219. Yoo OJ,
    1220. Yoon G,
    1221. Yoon SY,
    1222. Yorimitsu T,
    1223. Yoshikawa Y,
    1224. Yoshimori T,
    1225. Yoshimoto K,
    1226. You HJ,
    1227. Youle RJ,
    1228. Younes A,
    1229. Yu L,
    1230. Yu L,
    1231. Yu SW,
    1232. Yu WH,
    1233. Yuan ZM,
    1234. Yue Z,
    1235. Yun CH,
    1236. Yuzaki M,
    1237. Zabirnyk O,
    1238. Silva-Zacarin E,
    1239. Zacks D,
    1240. Zacksenhaus E,
    1241. Zaffaroni N,
    1242. Zakeri Z,
    1243. Zeh HJ 3rd.,
    1244. Zeitlin SO,
    1245. Zhang H,
    1246. Zhang HL,
    1247. Zhang J,
    1248. Zhang JP,
    1249. Zhang L,
    1250. Zhang L,
    1251. Zhang MY,
    1252. Zhang XD,
    1253. Zhao M,
    1254. Zhao YF,
    1255. Zhao Y,
    1256. Zhao ZJ,
    1257. Zheng X,
    1258. Zhivotovsky B,
    1259. Zhong Q,
    1260. Zhou CZ,
    1261. Zhu C,
    1262. Zhu WG,
    1263. Zhu XF,
    1264. Zhu X,
    1265. Zhu Y,
    1266. Zoladek T,
    1267. Zong WX,
    1268. Zorzano A,
    1269. Zschocke J and
    1270. Zuckerbraun B
    : Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8(4): 445-544, 2012. PMID: 22966490. DOI: 10.4161/auto.19496
    OpenUrlCrossRefPubMed
  24. ↵
    1. Sinha K,
    2. Das J,
    3. Pal PB and
    4. Sil PC
    : Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87(7): 1157-1180, 2013. PMID: 23543009. DOI: 10.1007/s00204-013-1034-4
    OpenUrlCrossRefPubMed
  25. ↵
    1. Lefrak EA,
    2. Pitha J,
    3. Rosenheim S and
    4. Gottlieb JA
    : A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32(2): 302-314, 1973. PMID: 4353012. DOI: 10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2
    OpenUrlCrossRefPubMed
  26. ↵
    1. Kong CY,
    2. Guo Z,
    3. Song P,
    4. Zhang X,
    5. Yuan YP,
    6. Teng T,
    7. Yan L and
    8. Tang QZ
    : Underlying the mechanisms of doxorubicin-induced acute cardiotoxicity: Oxidative stress and cell death. Int J Biol Sci 18(2): 760-770, 2022. PMID: 35002523. DOI: 10.7150/ijbs.65258
    OpenUrlCrossRefPubMed
  27. ↵
    1. Speyer JL,
    2. Green MD,
    3. Kramer E,
    4. Rey M,
    5. Sanger J,
    6. Ward C,
    7. Dubin N,
    8. Ferrans V,
    9. Stecy P and
    10. Zeleniuch-Jacquotte A
    : Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 319(12): 745-752, 1988. PMID: 3137469. DOI: 10.1056/NEJM198809223191203
    OpenUrlCrossRefPubMed
    1. Lipshultz SE,
    2. Rifai N,
    3. Dalton VM,
    4. Levy DE,
    5. Silverman LB,
    6. Lipsitz SR,
    7. Colan SD,
    8. Asselin BL,
    9. Barr RD,
    10. Clavell LA,
    11. Hurwitz CA,
    12. Moghrabi A,
    13. Samson Y,
    14. Schorin MA,
    15. Gelber RD and
    16. Sallan SE
    : The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351(2): 145-153, 2004. PMID: 15247354. DOI: 10.1056/NEJMoa035153
    OpenUrlCrossRefPubMed
  29. ↵
    1. Shimauchi T,
    2. Numaga-Tomita T,
    3. Ito T,
    4. Nishimura A,
    5. Matsukane R,
    6. Oda S,
    7. Hoka S,
    8. Ide T,
    9. Koitabashi N,
    10. Uchida K,
    11. Sumimoto H,
    12. Mori Y and
    13. Nishida M
    : TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. JCI Insight 2(15): e93358, 2017. PMID: 28768915. DOI: 10.1172/jci.insight.93358
    OpenUrlCrossRefPubMed
  30. ↵
    1. Kim KY,
    2. Park KI,
    3. Kim SH,
    4. Yu SN,
    5. Lee D,
    6. Kim YW,
    7. Noh KT,
    8. Ma JY,
    9. Seo YK and
    10. Ahn SC
    : Salinomycin induces reactive oxygen species and apoptosis in aggressive breast cancer cells as mediated with regulation of autophagy. Anticancer Res 37(4): 1747-1758, 2017. PMID: 28373437. DOI: 10.21873/anticanres.11507
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Ueno M,
    2. Kakinuma Y,
    3. Yuhki K,
    4. Murakoshi N,
    5. Iemitsu M,
    6. Miyauchi T and
    7. Yamaguchi I
    : Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo. J Pharmacol Sci 101(2): 151-158, 2006. PMID: 16766856. DOI: 10.1254/jphs.fp0050980
    OpenUrlCrossRefPubMed
  32. ↵
    1. Kostrzewa-Nowak D and
    2. Tarasiuk J
    : Bioreductive activation of antitumour drugs, doxorubicin and pirarubicin, does not affect their ability to induce apoptosis of sensitive and multidrug resistant leukaemia HL60 cells. Anticancer Res 41(3): 1429-1438, 2021. PMID: 33788734. DOI: 10.21873/anticanres.14900
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Ichikawa Y,
    2. Ghanefar M,
    3. Bayeva M,
    4. Wu R,
    5. Khechaduri A,
    6. Naga Prasad SV,
    7. Mutharasan RK,
    8. Naik TJ and
    9. Ardehali H
    : Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124(2): 617-630, 2014. PMID: 24382354. DOI: 10.1172/JCI72931
    OpenUrlCrossRefPubMed
  34. ↵
    1. Komatsu M,
    2. Kurokawa H,
    3. Waguri S,
    4. Taguchi K,
    5. Kobayashi A,
    6. Ichimura Y,
    7. Sou YS,
    8. Ueno I,
    9. Sakamoto A,
    10. Tong KI,
    11. Kim M,
    12. Nishito Y,
    13. Iemura S,
    14. Natsume T,
    15. Ueno T,
    16. Kominami E,
    17. Motohashi H,
    18. Tanaka K and
    19. Yamamoto M
    : The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12(3): 213-223, 2010. PMID: 20173742. DOI: 10.1038/ncb2021
    OpenUrlCrossRefPubMed
  35. ↵
    1. Mebratu Y and
    2. Tesfaigzi Y
    : How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle 8(8): 1168-1175, 2009. PMID: 19282669. DOI: 10.4161/cc.8.8.8147
    OpenUrlCrossRefPubMed
  36. ↵
    1. Yue J and
    2. López JM
    : Understanding MAPK signaling pathways in apoptosis. Int J Mol Sci 21(7): 2346, 2020. PMID: 32231094. DOI: 10.3390/ijms21072346
    OpenUrlCrossRefPubMed
  37. ↵
    1. Cagnol S and
    2. Chambard JC
    : ERK and cell death: mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J 277(1): 2-21, 2010. PMID: 19843174. DOI: 10.1111/j.1742-4658.2009.07366.x
    OpenUrlCrossRefPubMed
  38. ↵
    1. Mulcahy Levy JM and
    2. Thorburn A
    : Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27(3): 843-857, 2020. PMID: 31836831. DOI: 10.1038/s41418-019-0474-7
    OpenUrlCrossRefPubMed
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Effect of Chloroquine on Doxorubicin-induced Apoptosis in A549 Cells
KEISUKE SATO, NATSUKI OTA, SHOYA ENDO, AKIFUMI NAKATA, HIROSHI YAMASHITA, RYOSUKE TATSUNAMI
Anticancer Research Aug 2022, 42 (8) 4025-4035; DOI: 10.21873/anticanres.15899
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