Research ArticleExperimental Studies

Synergistic and Antagonistic Antiproliferative Effects of Ribociclib (Lee011) and Irinotecan (SN38) on Colorectal Cancer Cells

CHUNG-I HUANG, YI-KAI HUANG, HUI-MING LEE, JIAN-HAN CHEN, YU-CHIEH SU and PAI-MEI LIN
Anticancer Research May 2023, 43 (5) 1933-1941; DOI: https://doi.org/10.21873/anticanres.16353

Abstract

Background/Aim: Colorectal cancer (CRC) is one of the most common malignancies and cause of cancer-related deaths worldwide. The combination of chemotherapeutics working with different mechanisms enhances the therapeutic effects and delays the development of resistance. This study investigated the anticancer effect of the combination of ribociclib (LEE011) and irinotecan (SN38) on CRC cells. Materials and Methods: HT-29 and SW480 cells were treated with LEE011, SN38, or the combination of LEE011 and SN38. Cell viability and cell cycle distribution were analyzed. The expression of cell cycle- and apoptosis-related proteins was determined using western blot. Results: The combination of LEE011 and SN38 elicited a synergistic antiproliferative effect on HT-29 (PIK3CAP449T mutation) cells, and an antagonistic antiproliferative effect on SW480 (KRASG12V mutation) cells. LEE011 inhibited retinoblastoma protein (Rb) phosphorylation and led to G1 arrest in HT-29 and SW480 cells. SN38 treatment caused a significant increase in the phosphorylation levels of Rb, cyclin B1, and CDC2 in SW480 cells and induced S phase arrest. Furthermore, SN38 treatment increased the phosphorylation levels of p53 and activated caspase-3 and caspase-8 in HT-29 and SW480 cells. LEE011-induced G1 arrest contributed to its synergistic antiproliferative effect with SN38 in HT-29 cells through the down-regulation of the phosphorylation of Rb. In addition, it elicited an antagonistic effect with SN38 in SW480 cells by changing the phosphorylation levels of Rb and activating caspase-8. Conclusion: The effects of the combination of LEE011 and conventional chemotherapy drugs on CRC depend on the chemotherapy drug and the specific gene mutation harbored by tumor cells.

Key Words:

Colorectal cancer (CRC) is one of the most common malignancies, ranked third in incidence and second as the leading cause of cancer-related deaths globally (1). In 2020, 1.9 million CRC cases were diagnosed, and 0.9 million deaths occurred, which accounted for 10% of the incidence of all cancers and 9.4% of cancer-related deaths (2). According to aging projection, population growth, and human development, the new CRC cases will increase to 3.2 million in 2040 (2). Furthermore, the incidence of CRC in young adults (age at diagnosis <50 years) increased in some high-income countries (3). Unfortunately, approximately 25% of CRC patients are diagnosed at the metastasis stage with a poor prognosis, and more than 50% of CRC patients develop metastasis during follow up (4).

SN38 (irinotecan active metabolite), a DNA topoisomerase I inhibitor, is used in combination with 5-fluorouracil/leucovorin or oxaliplatin as a first- or second-line treatment for advanced CRC (5, 6). Although SN38 treatment has increased CRC patient longevity, resistance remains a significant problem that limits the efficacy of SN38 and triggers cancer metastasis and relapse (7). Additionally, SN38 produces severe side effects, including severe neutropenia and diarrhea, which are detrimental to the quality of life and compromise its use (8).

Dysregulation of cell cycle control leads to malignant transformation and accelerated tumor cell proliferation (9). The cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6)-retinoblastoma (Rb) pathway is a critical checkpoint for cell cycle progression. CDK4/6 binds to cyclin D1 to form an active complex, which phosphorylates the Rb protein thereby releasing the E2F transcription factor. This leads to G1/S transition of the cell cycle and commitment to cell division (10). In many human cancers, disruption of the cyclin-CDK complexes function provides a main driver for tumor cell proliferation (11). CDK4/6 inhibition has been investigated to restore the deregulated cell cycle progression and block cancer cell proliferation in a variety of tumor cells (12). LEE011, a CDK4/6 inhibitor, was developed by Novartis for the treatment of a wide variety of solid cancers, including breast cancer, melanoma, and neuroblastoma (13). The addition of LEE011 to existing anticancer therapies increases their efficacy.

Mutations and/or epigenetic dysregulations of cell cycle-related genes contribute to the tumorigenesis of CRC. Amplification of CDK4/6 in colon tumor and high CDK4 levels are observed in patients with CRC, indicating that CDK4/6 are potential targets of therapeutic agents to improve CRC treatment (14).

The studies of LEE011 in CRC are rare. Combination of LEE011 with the convention chemotherapeutic agent 5-FU and SHP2 inhibitor TNO155 synergistically reduced cell viability in colorectal cell lines and inhibited tumor growth in a CRC patient–derived xenografts, respectively (15, 16). In the current study, we assessed the efficacy of the combination of LEE011 with SN38 on the CRC cell lines HT-29 and SW480. We also explored the anticancer mechanism of the combination treatment using flow cytometry analysis and western blot.

Materials and Methods

Materials. SN-38 was purchased from Sigma-Aldrich (St. Louis, MO, USA). LEE011 was provided by the Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA). The CellTiter-Glo® One Solution Assay was obtained from Promega (Madison, WI, USA). Antibodies against phosphorylated Rb, p53, cyclin B1, CDC2, GAPDH, Rb, p53, cyclin B1, CDC2, Caspase 3 (D3R6Y), Caspase8 (1C12) and C-Caspase3 (D175) (5A1E) were procured from Cell Signaling Technology (Danvers, MA, USA).

Cell culture. HT-29 and SW480 cells were obtained from the American Type Culture Collection (Manassas, VA, USA). The HT-29 cells were maintained in McCoy’s 5A medium supplemented with 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA) and 1% antibiotic antimycotic solution. The SW480 cells were cultured in Leibovitz’s L-15 medium supplemented with 10% FBS and 1% antibiotic antimycotic solution. HT-29 and SW480 cells were incubated at 37°C with a 5% CO2 supplement.

Cell viability. HT-29 and SW480 cells were seeded at a density of 5×103 per well in 96-well plates for 24 h. The cells were treated with LEE011 or SN38 at the indicated concentrations for 24, 48, or 72 h. The cell viabilities were analyzed using the CellTiter-Glo® One Solution Assay (Promega, Madison, WI, USA) according to the manufacturer’s instructions. The luminescence was determined using Varioskan™ LUX multimode microplate reader (Thermo Fisher Scientific, Waltham, MA, USA).

Analysis of drug synergism. HT-29 and SW480 cells were seeded at a density of 5×103 per well in 96-well plates for 24 h. The cells were treated with LEE011, SN38, or their combination at the indicated concentrations for 24 or 48 h. The synergistic index was calculated as previously described (17, 18). The coefficient of drug interaction (CDI) was used to analyze the interaction between the pure compounds used as mixture. CDI was calculated as follows: CDI=%AB/(%A×%B). Synergistic was defined as CDI <1; additivity was defined as CDI=1; antagonistic was defined as CDI >1. A and B are the effects of each individual agent, and AB is the effect of the combination.

Cell cycle analysis. HT-29 and SW480 cells were seeded in a 6 cm plate at a density of 1×106 per well overnight. The cells were treated with LEE011, SN38 or their combination at the indicated concentrations. After 24 or 48 h of incubation, floating and adherent cells were collected through centrifugation, washed twice with ice-cold phosphate-buffer saline (PBS), and fixed with 75% ice-cold ethanol at 4°C overnight. The cells were subsequently centrifuged to remove ethanol, and the cell pellets were resuspended in PBS containing RNase at a density of 100 μg/ml. The samples were then stained with propidium iodide at a density of 40 μg/ml in PBS at 37°C for 30 min and analyzed using an LSR II flow cytometer (BD Biosciences, San Jose, CA, USA).

Western blot. Cell lysates were collected with RIPA lysis buffer (Thermo Fisher Scientific) after 24 or 48 h of treatment. The insoluble protein was removed through centrifugation, and the concentration of soluble protein was determined using a Bio-Rad protein assay kit (Hercules, CA, USA). An equal amount of protein was analyzed through 10% SDS–polyacrylamide gel electrophoresis and transferred to PVDF membranes and probed with specific antibodies. Blotting signals on the PVDF membrane were developed using an ECL detection kit (PerkinElmer, Waltham, MA, USA). The protein abundance of the samples was quantified using Image-J software (NIH, Bethesda, MD, USA) following densitometric scanning.

Statistical analysis. Data are presented as mean±standard deviation from at least three independent experiments. Statistically significant differences between the control and treatment groups were analyzed using Student’s t-test, and p-values less than 0.01 indicated significant differences.

Results

SN38 reduces the proliferation of colon cancer cells. HT-29 and SW480 cells were treated with SN38 at the 0.05, 0.25, 2, 10, or 50 μM for 24, 48, and 72 h. The results revealed that SN38 dose- and time-dependently reduced the cell proliferation in HT-29 and SW480 cells after 24- and 48-h treatment (Figure 1). The inhibitory effect of SN38 was higher in the HT-29 than that in SW480 cells at the same concentration.

Figure 1.
Figure 1.

Inhibitory effect of SN38 on the viability of HT-29 and SW480 cells. (A) HT-29 and (B) SW480 cells were treated with the indicated concentrations of SN38 for 24, 48, and 72 h. Cell viability was measured using MTS assay. Data were analyzed using Student’s t-test and expressed as mean±SD from three independent experiments. *p<0.01 compared with the control group.

LEE011 combined with SN38 elicited a synergistic anti-proliferation effect on HT-29 cells, but an antagonistic anti-proliferation effect on SW480 cells. LEE011 has been demonstrated to dose-dependently reduce the proliferation of human CRC cell lines HT-29 and SW480 (15). The effect of the treatment with the combination of LEE011 and SN38 on the proliferation of the human CRC cell lines HT-29 and SW480 was evaluated through a cell viability assay (Figure 2). The effect of combination treatment of the LEE011 and SN38 was further evaluated based on coefficient of drug interaction (CDI) values as described in Materials and Methods. The results showed that the CDI value of the combination treatment of 5 μM LEE011 and 10 μM SN38 on HT-29 cells was less than 1 (0.935), indicating that they elicited a synergistic inhibitory effect on HT-29 cells. However, the CDI value of the combination treatment of LEE011 and SN38 in SW480 cells was more than 1, which suggested that the effect of the combination treatment of LEE011 and SN38 was antagonistic on SW480 cells.

Figure 2.
Figure 2.

Effect of the combination treatment of SN38 and LEE011 on the viability of HT-29 and SW480 cells. (A) HT-29 and (B) SW480 cells were treated with indicated concentrations of SN38 and LEE011 for 24 or 48 h. Cell viability was determined using MTS assay. Data were analyzed using Student’s t-test and presented as mean±SD from three independent experiments. *p<0.01 compared with the control group.

LEE011 and SN38 treatment affected cell cycle arrest and proliferation-related proteins in CRC cells. The impact of LEE011 and SN38 on the cell cycle of HT-29 and SW480 cells was evaluated using flow cytometric analysis. HT-29 cells were treated with 5 μM LEE011, 10 μM SN38, or both for 24 h; SW480 cells were treated with 5 μM LEE011, 250 nM SN38, or both for 48 h. The results indicated that LEE011 treatment caused G1 phase arrest in HT-29 and SW480 cells (Figure 3). Following treatment with LEE011, the proportion of HT-29 and SW480 cells in the G1 phase increased significantly from 49.3% to 83.0% and from 54.0% to 75.2%, respectively. SN38 treatment induced S phase arrest in SW480 but not in HT-29 cells (Figure 3). Following treatment with SN38, the proportion of SW480 cells in the S phase increased from 20.6% to 91.9%, whereas no significant change in the distribution of HT-29 cells was observed after treatment with SN38. Treatment with the combination of LEE011 and SN38 arrested SW480 cells in the G1 phase (Figure 3B) but had no effect on the distribution of HT-29 cells when compared to control (Figure 3A). Following treatment with the combination of Lee011 and SN38, the proportion of SW480 cells in the G1 phase changed from 54.0% to 70.9%.

Figure 3.
Figure 3.

Flow cytometric analysis of the effect of SN38 and LEE011 on HT-29 and SW480 cells. The cell cycle distribution and the percentage of cell cycle distribution of (A) HT-29 and (B) SW480 cells was measured using flow cytometry after treatment with the indicated concentrations of SN38 and LEE011 for 24 or 48 h.

To clarify the regulatory mechanism underlying the cell cycle arrest caused by LEE011 and SN38, the expression and phosphorylation levels of cell cycle-related proteins, Rb, p53, and G2/M checkpoint proteins (cyclin B1 and CDC2) were analyzed using western blot. The western blot results showed that the phosphorylation of Rb, cyclin B1, and CDC2 was reduced in HT-29 and SW480 cells treated with LEE011. These results indicated that LEE011 inhibits Rb activity and leads to G1 arrest and further affects the activity of G2/M checkpoint-related proteins cyclin B/CDC2 in HT-29 and SW480 cells. The western blot results showed that treatment with SN38, significantly increased the phosphorylation levels of Rb, p53, cyclin B1, and CDC2 in SW480 cells, but only induced p53 phosphorylation levels in HT-29 cells. The western blot results were consistent with the results of cell cycle distribution of HT-29 and SW480 cells treated with SN38. The reduction in the levels of phosphorylated Rb as sell as cyclin B1 and CDC2 was lower in HT-29 cells treated with the combination of LEE011 and SN38 compared to that of cells treated with LEE011 alone. However, the expression of phosphorylated Rb, cyclin B1, and CDC2 was still significantly decreased in HT-29 cells treated with the combination of LEE011 and SN38 compared to the control (Figure 4A). These observations show that LEE011-induced G1 arrest contributed to its synergistic effect with SN38 against HT-29 proliferation. Compared with control and Lee011 alone, treatment of SW480 cells with the combination of LEE011 and SN38 resulted in a significant increase in the phosphorylation levels of Rb, indicating that the antiproliferative effect of LEE011 was reduced when combined with SN38 in SW480 cells (Figure 4B).

Figure 4.
Figure 4.

Effect of SN38 and LEE011 on the expression of cell cycle-related proteins in (A) HT-29 and (B) SW480 cells. Cells were treated with SN38 and LEE011 at the indicated concentrations for 24 or 48 h. Cell lysates were collected and analyzed using western blot. GAPHD served as the loading control. Data were analyzed using Student’s t-test and presented as mean±SD. Asterisks indicate significant differences. *p<0.01 compared with the control group.

LEE011 and SN38 treatment induced apoptosis in CRC cells. To conduct apoptosis, cells must activate the caspase family of enzymes (19). We analyzed the protein levels of the cleaved form of caspases-3 and capases-8 in HT-29 and SW480 cells treated with LEE011, SN-38, or both drugs using western blot. SN38 alone and the combination treatment of LEE011 with SN38 induced cleavage of full-length caspase-8 into cleaved caspase-8, and cleavage of full-length caspase-3 into the active dimeric form of cleaved caspase-3, respectively (Figure 5A and C). The results showed that treatment with SN38 alone or LEE011 and SN38 combination significantly elevated the cleaved caspase-8 levels, approximately 4.3-fold over the control in HT29 cells (Figure 5B). The full-length caspase-3 levels were unaffected, but the cleaved caspase-3 protein levels were increased by approximately 13.7- and 8.1-fold increment over the control in HT29 cells, respectively (Figure 5B). The cleaved caspase-8 levels and caspase-3 level were elevated about 5.1 and 7.1-fold over the control in SW480 when treat with SN38 alone. Furthermore, treatment of SW480 cells with the combination of SN38 with LEE011 increased the levels of the cleaved caspase-8 and caspase-3 by approximately 1.9-fold and 2.6-fold over the control, respectively (Figure 5D). In addition, the levels of cleaved caspase-3 and caspase-8 in SW480 cells treated with the combination of LEE011 and SN38 were significantly reduced compared with those in SW480 cells treated with SN38 alone. All protein levels were normalized to GAPDH levels. These observations revealed that SN38 alone and its combination with LEE011 induced apoptosis in HT29 and SW480 cells, but the apoptosis effect of SN38 was attenuated when combined with LEE011 in SW480 cells. These results were consistent with the antagonistic effect of LEE011 and SN38 on the reduction of the proliferation of SW480 cells.

Figure 5.
Figure 5.

Effect of SN-38 and LEE011 on the expression of apoptosis-related proteins in (A, B) HT-29 and (C, D) SW480 cells. Cells were treated with SN38 and LEE011 at the indicated concentrations for 24 or 48 h. Cell lysates were collected and analyzed using western blot. GAPHD served as the loading control. Data were analyzed using Student’s t-test and presented as mean±SD. Asterisks indicate significant differences. *p<0.01 compared with the control group.

Discussion

SN38, a first- or second-line chemotherapy agent used in advanced CRC, is combined with 5-fluorouracil (5-FU)/leucovorin or capecitabine against advanced CRC (20). The combination regimens provide a survival benefit to CRC patients with metastatic colorectal cancer. However, resistance and severe side effects limit the efficacy of SN38 (7, 8). Therefore, developing alternative combinations of drugs to provide additional therapeutic options is important. LEE011, a specific CDK4/6 kinase inhibitor, is approved for the first line treatment of HR+/HER2 breast cancer (13). In the present study, the anticancer activity of LEE011 as a combination with SN38 was investigated in the CRC cell lines HT-29 and SW480. Our results demonstrated that the combination treatment of Lee011 and SN38 elicited a synergistic inhibitory effect on the proliferation of HT-29 cells, but an antagonistic inhibitory effect on the proliferation of SW480 cells.

The mechanism of the anti-cancer activity of SN38 involves inhibition of topoisomerase I enzyme and DNA strand breakage, acting on the S and G2 phases of the cell cycle (20). In the present study, flow cytometry results indicated that SN38 induced S phase arrest in SW480 cells. Western blot results confirmed that phosphorylation levels of Rb, cyclin B1 and CDC2 were significantly increased by SN38 in SW480 cells. The levels of phosphorylated p53 and those of active forms of cleaved caspase-3 and caspase-8 were induced by SN38 in HT-29 and SW480 cells. All these results indicate that in CRC, the proliferation of cells was inhibited by SN38 through cell cycle disturbance, activation of p53, and apoptosis.

When HT-29 and SW480 cells were treated with different doses of LEE011, their viability was significantly reduced by inhibiting Rb phosphorylation and leading the G1 arrest and further affecting the expression of G2/M checkpoint related proteins cyclin B/CDC2.

Upon treatment of HT-29 cells with the combination of LEE011 with SN38, LEE011-induced G1 arrest contributed to its synergistic effect with SN38 against HT-29 proliferation. Whereas upon treatment of SW480 cells with the combination of LEE011 with SN38, the antiproliferation effect of LEE011 and the apoptosis effect of SN38 were attenuated. These effects caused the antagonistic effect on the reduction of the proliferation between LEE011 and SN38 in SW480 cells.

The tolerable profile and therapeutic potential of LEE011 for a variety of cancer types makes it an important drug for the combination with other targeted therapies to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance (13). However, some studies suggest combinations of CDK inhibitors with cytotoxic chemotherapy could be antagonistic since the majority of conventional chemotherapeutics target actively cycling cells (21, 22). The combination of LEE011 and 5-FU elicited synergistic inhibitory effects on HT-29 and SW480 cells (15). In our present study, the combination of LEE011 and SN38 elicited a synergistic inhibitory effect on HT-29 (PIK3CAP449T mutation) cells, and an antagonistic inhibitory effect on SW480 (KRASG12V mutation) cells. Our study suggests the effects of combination of LEE011 and conventional chemotherapy drugs in CRC are associated with the drugs and the tumor cell type harboring different mutations. Our work provides a useful information for the combination of LEE011 with cytotoxic chemotherapeutic drugs in CRC preclinical treatment.

Acknowledgements

This study was supported by a grant from the E-Da Cancer Hospital (EDCHP107008, EDCHP109003) and the E-Da Hospital (EDAHC111007).

Footnotes

  • Authors’ Contributions

    Huang CI, Huang YK, and Lin PM: conception and design of the study. Huang CI, Huang YK, Lee HM, Chen JH, and Su YC: interpretation of the data. Huang CI, Huang YK, and Lin PM: drafting and editing of the article. All Authors reviewed and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that no competing interests exist in relation to this study.

  • Received February 13, 2023.
  • Revision received March 5, 2023.
  • Accepted March 8, 2023.

References

  1. ↵
    1. Sung H,
    2. Ferlay J,
    3. Siegel RL,
    4. Laversanne M,
    5. Soerjomataram I,
    6. Jemal A and
    7. Bray F
    : Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3): 209-249, 2021. PMID: 33538338. DOI: 10.3322/caac.21660
    OpenUrlCrossRefPubMed
  2. ↵
    1. Xi Y and
    2. Xu P
    : Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 14(10): 101174, 2021. PMID: 34243011. DOI: 10.1016/j.tranon.2021.101174
    OpenUrlCrossRefPubMed
  3. ↵
    1. Siegel RL,
    2. Torre LA,
    3. Soerjomataram I,
    4. Hayes RB,
    5. Bray F,
    6. Weber TK and
    7. Jemal A
    : Global patterns and trends in colorectal cancer incidence in young adults. Gut 68(12): 2179-2185, 2019. PMID: 31488504. DOI: 10.1136/gutjnl-2019-319511
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Effendi-Ys R
    : Colonoscopy, biomarkers, and targeted therapy in colorectal cancer. Acta Med Indones 54(3): 476-486, 2022. PMID: 36156476.
    OpenUrlPubMed
  5. ↵
    1. Jiang W,
    2. Liu Q,
    3. Yang D and
    4. Yang SB
    : The efficacy of irinotecan supplementation for colorectal cancer: A meta-analysis of randomized controlled studies. Medicine (Baltimore) 101(41): e28090, 2022. PMID: 36254072. DOI: 10.1097/MD.0000000000028090
    OpenUrlCrossRefPubMed
  6. ↵
    1. Liu W,
    2. Chen FL,
    3. Wang K,
    4. Bao Q,
    5. Wang HW,
    6. Jin KM and
    7. Xing BC
    : Irinotecan- vs oxaliplatin-based regimens for neoadjuvant chemotherapy in colorectal liver metastasis patients: A retrospective study. World J Gastrointest Surg 14(9): 904-917, 2022. PMID: 36185567. DOI: 10.4240/wjgs.v14.i9.904
    OpenUrlCrossRefPubMed
  7. ↵
    1. Ozawa S,
    2. Miura T,
    3. Terashima J and
    4. Habano W
    : Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review. Cancer Drug Resist 4(4): 946-964, 2021. PMID: 35582377. DOI: 10.20517/cdr.2021.82
    OpenUrlCrossRefPubMed
  8. ↵
    1. Paulík A,
    2. Nekvindová J and
    3. Filip S
    : Irinotecan toxicity during treatment of metastatic colorectal cancer: focus on pharmacogenomics and personalized medicine. Tumori 106(2): 87-94, 2020. PMID: 30514181. DOI: 10.1177/0300891618811283
    OpenUrlCrossRefPubMed
  9. ↵
    1. Otto T and
    2. Sicinski P
    : Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 17(2): 93-115, 2017. PMID: 28127048. DOI: 10.1038/nrc.2016.138
    OpenUrlCrossRefPubMed
  10. ↵
    1. Ingham M and
    2. Schwartz GK
    : Cell-cycle therapeutics come of age. J Clin Oncol 35(25): 2949-2959, 2017. PMID: 28580868. DOI: 10.1200/JCO.2016.69.0032
    OpenUrlCrossRefPubMed
  11. ↵
    1. Meeran SM and
    2. Katiyar SK
    : Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci 13: 2191-2202, 2008. PMID: 17981702. DOI: 10.2741/2834
    OpenUrlCrossRefPubMed
  12. ↵
    1. Huang J,
    2. Zheng L,
    3. Sun Z and
    4. Li J
    : CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review). Int J Mol Med 50(4): 128, 2022. PMID: 36043521. DOI: 10.3892/ijmm.2022.5184
    OpenUrlCrossRefPubMed
  13. ↵
    1. Tripathy D,
    2. Bardia A and
    3. Sellers WR
    : Ribociclib (LEE011): Mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors. Clin Cancer Res 23(13): 3251-3262, 2017. PMID: 28351928. DOI: 10.1158/1078-0432.CCR-16-3157
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Thoma OM,
    2. Neurath MF and
    3. Waldner MJ
    : Cyclin-dependent kinase inhibitors and their therapeutic potential in colorectal cancer treatment. Front Pharmacol 12: 757120, 2021. PMID: 35002699. DOI: 10.3389/fphar.2021.757120
    OpenUrlCrossRefPubMed
  15. ↵
    1. Lin PM,
    2. Lee HM,
    3. Huang CI,
    4. Tai TS,
    5. Chen JH,
    6. Chen CI and
    7. Su YC
    : Synergistic antiproliferative effect of ribociclib (LEE011) and 5-fluorouracil on human colorectal cancer. Anticancer Res 40(11): 6265-6271, 2020. PMID: 33109564. DOI: 10.21873/anticanres.14647
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Liu C,
    2. Lu H,
    3. Wang H,
    4. Loo A,
    5. Zhang X,
    6. Yang G,
    7. Kowal C,
    8. Delach S,
    9. Wang Y,
    10. Goldoni S,
    11. Hastings WD,
    12. Wong K,
    13. Gao H,
    14. Meyer MJ,
    15. Moody SE,
    16. LaMarche MJ,
    17. Engelman JA,
    18. Williams JA,
    19. Hammerman PS,
    20. Abrams TJ,
    21. Mohseni M,
    22. Caponigro G and
    23. Hao HX
    : Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res 27(1): 342-354, 2021. PMID: 33046519. DOI: 10.1158/1078-0432.CCR-20-2718
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Della Corte CM,
    2. Bellevicine C,
    3. Vicidomini G,
    4. Vitagliano D,
    5. Malapelle U,
    6. Accardo M,
    7. Fabozzi A,
    8. Fiorelli A,
    9. Fasano M,
    10. Papaccio F,
    11. Martinelli E,
    12. Troiani T,
    13. Troncone G,
    14. Santini M,
    15. Bianco R,
    16. Ciardiello F and
    17. Morgillo F
    : SMO gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin Cancer Res 21(20): 4686-4697, 2015. PMID: 26124204. DOI: 10.1158/1078-0432.CCR-14-3319
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Soica C,
    2. Oprean C,
    3. Borcan F,
    4. Danciu C,
    5. Trandafirescu C,
    6. Coricovac D,
    7. Crăiniceanu Z,
    8. Dehelean CA and
    9. Munteanu M
    : The synergistic biologic activity of oleanolic and ursolic acids in complex with hydroxypropyl-γ-cyclodextrin. Molecules 19(4): 4924-4940, 2014. PMID: 24747649. DOI: 10.3390/molecules19044924
    OpenUrlCrossRefPubMed
  19. ↵
    1. Kuo HM,
    2. Tseng CC,
    3. Chen NF,
    4. Tai MH,
    5. Hung HC,
    6. Feng CW,
    7. Cheng SY,
    8. Huang SY,
    9. Jean YH and
    10. Wen ZH
    : MSP-4, an antimicrobial peptide, induces apoptosis via activation of extrinsic Fas/FasL- and intrinsic mitochondria-mediated pathways in one osteosarcoma cell line. Mar Drugs 16(1): 8, 2018. PMID: 29301308. DOI: 10.3390/md16010008
    OpenUrlCrossRefPubMed
  20. ↵
    1. Reyhanoglu G and
    2. Smith T
    : Irinotecan. StatPearls [Internet], 2022. PMID: 32119328.
  21. ↵
    1. Jin D,
    2. Tran N,
    3. Thomas N and
    4. Tran DD
    : Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity. PLoS One 14(10): e0223555, 2019. PMID: 31600301. DOI: 10.1371/journal.pone.0223555
    OpenUrlCrossRefPubMed
  22. ↵
    1. Pikman Y,
    2. Alexe G,
    3. Roti G,
    4. Conway AS,
    5. Furman A,
    6. Lee ES,
    7. Place AE,
    8. Kim S,
    9. Saran C,
    10. Modiste R,
    11. Weinstock DM,
    12. Harris M,
    13. Kung AL,
    14. Silverman LB and
    15. Stegmaier K
    : Synergistic drug combinations with a CDK4/6 inhibitor in T-cell acute lymphoblastic leukemia. Clin Cancer Res 23(4): 1012-1024, 2017. PMID: 28151717. DOI: 10.1158/1078-0432.CCR-15-2869
    OpenUrlAbstract/FREE Full Text
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Synergistic and Antagonistic Antiproliferative Effects of Ribociclib (Lee011) and Irinotecan (SN38) on Colorectal Cancer Cells
CHUNG-I HUANG, YI-KAI HUANG, HUI-MING LEE, JIAN-HAN CHEN, YU-CHIEH SU, PAI-MEI LIN
Anticancer Research May 2023, 43 (5) 1933-1941; DOI: 10.21873/anticanres.16353
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