Research ArticleExperimental Studies
Open Access

Antitumor Activity of Symmetrical Selenoesters in Doxorubicin Resistant Breast Cancer

BALINT RACZ, ERZSEBET KRISTOF, ANNAMARIA KINCSES, ENRIQUE DOMINGUEZ-ALVAREZ and GABRIELLA SPENGLER
Anticancer Research November 2023, 43 (11) 4865-4872; DOI: https://doi.org/10.21873/anticanres.16683

Abstract

Background/Aim: Previously, selenocompounds (Se-compounds) and in particular selenoesters have shown promising anticancer activities. Since molecular symmetry can enhance the anticancer activity, nine symmetrical selenoesters (Se-esters) have been designed as novel, potentially active anticancer agents against doxorubicin resistant breast cancer cells. Materials and Methods: To assess the biological effects of the symmetrical Se-esters, the antiproliferative activity was determined on sensitive MCF-7 and doxorubicin resistant KCR breast cancer cell lines. The interaction of the derivatives with doxorubicin was evaluated by checkerboard combination assay on KCR cells. Furthermore, apoptosis induction and ATPase activity in the presence of Se-esters were also determined on KCR cells. Results: The symmetrical derivatives showed a noteworthy antiproliferative activity, with two of them showing IC50 values in submicromolar concentration on MCF-7 cells. In addition, some derivatives showed selectivity towards the resistant KCR cells. The combination of most of them with doxorubicin resulted in synergistic interaction, and all Se-esters could induce early and late apoptosis in KCR cells. Finally, the compounds affected the ATPase activity of ABCB1 (P-gp). Conclusion: The symmetrical Se-esters showed potent anticancer activity, according to in vitro tests. Further research needs to be performed to obtain similar derivatives with a better activity and selectivity, and to ascertain the potential application of these Se-containing compounds using in vivo systems.

Key Words:

Breast cancer is still a leading cause of cancer-related death in women (1). Besides surgery and radiotherapy, the treatment of breast cancer involves anthracycline- (e.g., Doxorubicin, Epirubicin) or taxane-based (e.g., Paclitaxel, Docetaxel) classic chemotherapeutics (2). Additionally, based on the human epidermal growth factor receptor-2 (HER-2) status and the hormonal receptor status, targeted drugs (e.g., Trastuzumab) and hormonal therapy (e.g., Tamoxifen, Fulvestrant) may be used. However, therapy resistance may develop during multimodal treatment, leading to disease progression and to the emergence of metastatic breast cancer (MBC). Resistant tumors and MBC pose a significant threat because of the poor response rates to the few available therapeutic alternatives. Various models describe tumor drug resistance; in the conventional model rare cells with genetic alterations that grant drug resistance can survive and proliferate after the chemotherapeutic treatment (3). According to the stem cell concept, a subpopulation of highly resistant cancer stem cells (CSCs) maintains the tumorous tissue. Multidrug resistance (MDR) is a natural attribute of CSCs due to their slow cell-cycle kinetics and because of the over-expression of ATP-binding cassette (ABC) transporters, such as ABCB1 or P-glycoprotein (P-gp), and genes related to MDR (3).

Reactive oxygen species (ROS) generated by the partial reduction of oxygen derivatives from multiple endogenous (e.g., mitochondria) and exogenous (e.g., drugs and radiation) sources play a significant role both in the normal function of cells and in cancer (4). In cancerous cells, because of increased metabolic activity, mitochondrial dysfunction and oncogenic signaling, the basal ROS levels are higher than in normal cells contributing to the progression and recurrence of cancer. Furthermore, to reduce the levels of ROS and evade cell death, cancer cells up-regulate their antioxidant defense systems, thus also contributing to the development of MDR (5). Therefore, targeting the redox homeostasis of cancer cells may be an attractive approach to enhance the toxicity of chemotherapeutics and to re-sensitize resistant cancer cells (6).

In numerous studies, selenium (Se) and Se-containing compounds have been reported to possess various beneficial activities, especially in cancer (7-11). Se-compounds achieve their anticancer effect through the modulation of redox homeostasis, which may modulate cell signaling and autophagy, and induce apoptosis and cell cycle arrest. The biological activity of Se and its derivatives is determined by their concentration and chemical form, the presence of different pharmacophores in the compound, and the metabolic activity of the target cell. Numerous synthetic Se-derivatives have demonstrated promising anticancer activities. Among them, selenoesters (Se-esters) previously prepared by our group have shown efflux pump inhibiting and chemosensitizing activity in several in vitro studies (12). Herein, we evaluate the cytotoxic and chemosensitizing activity on doxorubicin sensitive and doxorubicin resistant breast cancer cells lines exerted by symmetrical Se-esters containing different functional groups in the terminal alkyl moieties bound to the selenium atom.

Materials and Methods

Compounds. Nine symmetrical derivatives containing two or three selenoester functional groups were tested (Figure 1). Of these, three were 1,4-disubstituted derivatives (compounds Se-X1), three 1,3-disubstituted derivatives (compounds Se-X2), and three 1,3,5-trisubstituted derivatives (compounds Se-X3). They have different functionalities in the alkyl moiety bound to the selenium atom: each set of compounds has a methylketone derivative (compounds Se-KY), a methylcarbonyl derivative (compounds Se-EY) and a cyano derivative (compounds Se-CY) (Figure 1). The target derivatives were resynthesized following a procedure described previously (13) and had a purity suitable to be tested in biological assays, according to the elemental analysis results.

Figure 1.
Figure 1.

Chemical structures of the symmetrical selenocompounds evaluated.

Cell cultures. The doxorubicin sensitive parent human breast cancer cell line MCF-7 (ATCC ® HTB-22) and its doxorubicin adapted resistant subline KCR, and the normal MRC-5 (ATCC CCL-171) human embryonic lung fibroblast cell line were purchased from LGC Promochem (Teddington, UK). The cell lines were cultured in EMEM medium, as described previously (14).

Assay for antiproliferative activity. The effects of increasing concentrations of the compounds on cell proliferation were tested in 96-well flat-bottomed microtiter plates (Sarstedt, Nümbrecht, Germany). The adherent breast cancer cell lines (6×103 cells/well) and the human embryonic lung fibroblast cell line (6×103 cells/well) were seeded in EMEM medium (Sigma, Steinheim, Germany) in 96-well flat-bottomed microtiter plates for 4 hours before the assay. The two-fold serial dilutions of the compounds were made in a separate plate starting from 100 μM, and then were transferred to the plate wells containing the corresponding adherent cell line. Culture plates were incubated at 37°C for 72 h and 20 μl of MTT (thiazolyl blue tetrazolium bromide, Sigma-Aldrich, St Louis, MO, USA) solution (from a 5 mg/ml stock solution) were added to each well and the assay was completed as described earlier (14). IC50 values and the standard deviation (SD) were calculated from the results of triplicate experiments using GraphPad Prism software version 5.00 for Windows with nonlinear regression curve fit (GraphPad Software, San Diego, CA, USA).

Checkerboard combination assay. A checkerboard microplate method was applied to study the effect of interactions between the compounds and the chemotherapeutic drug doxorubicin. The assay was carried out on KCR human breast cancer cell line (15). The final concentration of the compounds and doxorubicin used in the combination experiment was chosen in accordance with their antiproliferative activity towards this cell line (IC50 value). The dilutions of doxorubicin in the microtiter plate were made in a horizontal direction in 100 μl and the dilutions of the compounds vertically in 50 μl volume. Then, 6×103 KCR cells in 50 μl of the medium were added to each well, except for the medium control wells. The plates were incubated for 72 h at 37°C in 5% CO2 atmosphere. The cell growth rate was determined after MTT staining (14). Combination index (CI) values at 50% of the growth inhibition dose (ED50) were determined using CompuSyn software (ComboSyn, Inc., Paramus, NJ, USA) to plot four to five data points at each ratio. CI values were determined using the median-effect equation, according to the Chou–Talalay method, where CI<1, CI=1, and CI>1 refer to synergism, additive effect (or no interaction), and antagonism, respectively (16, 17).

Apoptosis assay. The ability of symmetrical Se-esters to induce apoptosis was evaluated in the doxorubicin resistant KCR subline using Annexin V-fluorescein isothiocyanate (FITC) Apoptosis Detection Kit (Calbiochem, Merck KGaA, Darmstadt, Germany) with FITC-labelled annexin V and propidium iodide (PI). The density of the cell suspensions was adjusted to approximately 1×106 cells/ml. The cell suspension was distributed into 0.5 ml aliquots (5×105 cells) to a 24-well microplate and the compounds were added at a final concentration of 1 μM (Se-K1, -K2, -K3 and Se-C1, -C2, -C3) and 4 μM (Se-E1, -E2, -E3). The apoptosis inducer 12H-benzo[α]phenothiazine (M627) was applied as a positive control at 20 μM. The cells were incubated in the presence of the compounds for 3 h at 37°C. The samples were then centrifuged, the culture medium was discarded, the cells were washed with phosphate-buffered saline and afterwards fresh medium was added to the cells. The 24-well plates were incubated overnight at 37°C in a 5% CO2 atmosphere. On the following day, the samples were stained and analyzed using flow cytometry (14). The staining could visualize the necrotic (Q1: annexin V−/PI+), viable (Q4: annexin V−/PI−), early apoptotic (Q3: annexin V+/PI−), and late apoptotic (Q2: annexin V+/PI+) cells. The fluorescence of cell populations was immediately analyzed using a CyFlow® flow cytometer (Partec, Münster, Germany).

ATPase activity assay. The P-glycoprotein ATPase assay was performed using the P-gp-Glo™ Assay System (Promega, Madison, WI, USA) in the presence of the selenocompounds (18). The luminescent signals were detected with a CLARIOstar Plus plate reader (BMG Labtech, Ortenberg, Germany) at 580 nm. The relative ATPase activity was determined based on the ratio between the luminescence measured of the P-gp ATPase activity of each compound and the basal P-gp ATPase activity as follows:

Embedded Image

Results

Antiproliferative activity. The most potent antiproliferative activity was exerted by ketone-selenoesters: Se-K1 was more toxic on the resistant KCR cells, whereas Se-K2 and Se-K3 could inhibit the proliferation of the sensitive cell line in submicromolar concentrations (Table I). The methyloxycarbonyl-selenoesters were less toxic, however Se-E3 had collateral sensitivity effect being more toxic to the resistant KCR cells. Two derivatives of the nitrile-selenoesters were more active on the resistant cells, Se-C3 showed collateral sensitivity (IC50MCF-7: 16.82 μM; IC50KCR: 4.22 μM). None of the nine investigated selenoesters showed selective toxicity towards cancer cells (Table I).

View this table:
Table I.

Antiproliferative effect of symmetrical selenoesters on MCF-7 and KCR cells.

Combined effect with doxorubicin. The interaction of the selenoesters with doxorubicin in KCR cells was investigated using a checkerboard assay to monitor the potential interaction between the selenoesters with a clinically available anticancer drug (Table II). With the exception of Se-K1, the derivatives showed a synergistic interaction with doxorubicin. The strongest interaction was observed with Se-C3 because the combination index (CI) was the lowest (CI=0.256) (Table II). Interestingly, these selenoesters were tested on resistant Colo 320 (ATCC-CCL-220.1) colon adenocarcinoma cells expressing ABCB1 and LRP and Se-C3, the most potent derivative in our assay, exerted antagonistic interaction with doxorubicin. In addition, other selenoesters with nitrile moieties (Se-C1 and Se-C2) exhibited antagonism on Colo 320 cells (19).

View this table:
Table II.

Combined effect of the symmetrical selenoesters and doxorubicin on resistant KCR breast cancer cells.

Apoptosis induction. Apoptosis resistance is considered one of the hallmarks of cancer and is involved in cancer multidrug resistance. In breast cancer, the impaired apoptosis signaling can support the survival of tumor cells (20). For instance, DNA damage, ROS, and endoplasmic reticulum (ER) stress can activate the intrinsic mitochondrial pathway of apoptosis (21). It was confirmed by our previous study that ketone-selenoesters (Se-K1, -K2, -K3) and nitrile-selenoesters (Se-C1, -C2, -C3) were potent inhibitors of the ABCB1 efflux protein, whereas the selenoesters functionalized with methyl ester moieties (Se-E1, -E2, -E3) showed no effect on ABCB1 (19). Since it was verified that ABCB1 is involved in the inhibition of caspase-mediated apoptosis (22), we hypothesized that certain selenoesters could also act as apoptosis inducers in KCR cells. In order to prove the apoptosis inducing activity of selenocompounds on the doxorubicin-resistant KCR cell line (15, 23) over-expressing the ABCB1 efflux protein (P-gp), apoptosis induction assay was performed applying 3 hours of incubation in the presence of the tested selenocompounds. Based on the results obtained, all the selenoesters induced early and late apoptosis at the tested concentrations to nearly the same extent as the positive control M627 at 20 μM (Table III). The most pro-apoptotic compound was methylcarbonyl selenoester Se-E2, which showed higher induction of early and late apoptosis than the reference M627. In addition, methylcarbonyl selenoester Se-E1 and methylketone selenoesters Se-K2 and Se-K3 were less pro-apoptotic than the reference compound but they could trigger apoptotic events (early plus late) in more than the half of the gated cells (Figure 2). The apoptosis inducing activity of the investigated compounds may be the result of the combined effect of different mechanisms. Increased ROS and endoplasmic reticulum stress may activate the intrinsic apoptotic pathway, additionally, changes in polyamine metabolism and efflux pump inhibition may contribute to the apoptosis inducing effects of symmetrical selenoesters (22, 24).

View this table:
Table III.

Apoptosis induction in the KCR cell line by symmetrical selenoesters.

Figure 2.
Figure 2.

Apoptosis induction in KCR cell line by symmetrical selenoesters Se-E1 and Se-E2. 12H-benzo[α]phenothiazine (M627) was applied as a positive control. Cell populations: necrotic (Q1: annexin V−/PI+), viable (Q4: annexin V−/PI−), early apoptotic (Q3: annexin V+/PI−), and late apoptotic (Q2: annexin V+/PI+) cells. PI: Propidium iodide.

ATPase activity of symmetrical selenoesters. To elucidate the compounds’ activity on ABCB1 (P-gp) as well as the link between ABCB1 inhibition and apoptosis induction, the ATPase activity of the selenoesters was investigated at 25 μM using recombinant human P-gp membranes. By comparing the basal activity to the effect observed in the presence of selenoesters, the compounds can be ranked as stimulators, inhibitors or neutral. Out of the nine derivatives, one ketone and two methyl selenoesters (Se-K1, Se-E1, Se-E2) were inhibitors of the P-gp ATPase activity, because their ΔRLU (delta relative luminescence unit) was lower than that of the basal activity (Figure 3). Surprisingly, the methyl-ester derivative Se-E3 stimulated the P-gp ATPase activity and the nitriles (Se-C1, Se-C2, Se-C3) previously determined as ABCB1 modulators (19) were P-gp ATPase stimulators in this assay.

Figure 3.
Figure 3.

P-gp ATPase activity of selenocompounds. ΔRLUTC>ΔRLUbasal: the test compound is stimulator of Pgp ATPase activity. ΔRLUTC=ΔRLUbasal: the test compound has no effect on Pgp ATPase activity. ΔRLUTC<ΔRLUbasal: the test compound is an inhibitor of Pgp ATPase activity. TC: Test compound.

Discussion

It has been reported that selenides and diselenides possess antioxidant, pro-oxidant, redox-modulating, chemopreventive, and anticancer activities (25). Different studies indicate that molecular symmetry may enhance the anticancer activity of cytotoxic agents (26) and specific compounds that contain selenium and possess symmetrical structure e.g., alkylseleno imidocarbamates (27) and symmetrical selenoureas (28) have been reported to have promising anticancer effects. Therefore, a new series of symmetrical selenoesters has been designed, synthesized and tested as novel anticancer agents. These symmetrical selenoesters exhibit a symmetrical structure due to the presence of a central aromatic core substituted by two or three identical selenoester chains functionalized with ketones, methyl esters or nitriles. These derivatives were tested previously on sensitive and ABCB1 expressing colon adenocarcinoma cell lines, and were found to be remarkable inhibitors of the ABCB1 efflux pump and apoptosis inducers in the ABCB1 expressing cell line (13, 19). In addition, these derivatives demonstrated noteworthy antibacterial, anti-biofilm, and antifungal effects (29, 30).

The current study focused on the anticancer activity of the symmetrical derivatives on sensitive and ABCB1 over-expressing resistant breast cancer cell lines confirming the antitumor potency and possible collateral sensitivity effect of the symmetrical selenoesters. Apparently, our experimental results suggest that the symmetry in the molecular structure can amplify the activity of the molecule, at least for this class of selenocompounds. The most potent inhibition of proliferation was measured in the presence of ketone-selenoesters and the derivative Se-K1 exhibited collateral sensitivity being more potent on the resistant, ABCB1 over-expressing KCR cell line. This activity is related to the ROS generating properties of the compounds as suggested formerly by transcriptomic data on colon adenocarcinoma cells (19). Furthermore, all symmetrical derivatives induced early and late apoptosis in KCR cells that can also be explained by the pro-oxidant activity of the selenoesters. Except the derivative Se-K1, all selenoesters acted synergistically with doxorubicin on KCR cells. It was supposed that the inhibition of the MDR efflux pump ABCB1 (P-gp) could explain the apoptosis inducing effect of the derivatives, however only three derivatives (Se-K2, Se-E1, Se-E2) proved to be P-gp ATPase inhibitors. Therefore, the mode of action of the symmetrical selenoesters is complex and the symmetrical structure including the presence of Se-atoms is essential for their exceptional anticancer activity (31).

Conclusion

Our investigations show that symmetrical selenoesters may be promising candidates in the search of novel anticancer agents. Several intertwined factors might contribute to the observed anticancer effects. Se-esters may be metabolized, and this can increase ROS production in cancer cells, which may lead to changes in gene expression and apoptosis induction. Furthermore, transcriptomic data suggests that Se-esters may interfere with additional metabolic pathways. By down-regulating ERN1, Se-esters may impair the unfolded protein response (32) and as a result of ODC1 down-regulation the polyamine pathway (33) may be disturbed. These changes in cancer metabolism may lead to alterations of oncogenic signaling that may inhibit tumor progression and metastasis. Se-esters may be beneficial as adjuvants in case of ABCB1 over-expressing tumors due to their efflux pump inhibitory activity, although the exact mechanism of efflux pump inhibition exerted by Se-esters is unclear. It is possible that efflux pump inhibition is based on direct interaction and a result of the metabolic alterations and cell signaling in cancer cells. However, there may be pitfalls caused by the application of Se-esters, since cancer is a heterogenous disease. It is unclear whether the symmetrical Se-esters function as pro-drugs and need metabolic activation to exert their anticancer effects, which may be an obstacle when targeting hypoxic and metabolically less active cancer cells. Therefore, further investigations are needed to evaluate the anticancer effects of symmetrical Se-esters in more complex cancer models and to study the interaction with ABCB1 efflux pump.

Overall, the potent anticancer activity of symmetrical Se-esters makes them promising candidates in the search of novel anticancer agents. Nevertheless, these in vitro results should be evaluated by more in-depth studies, such as additional in vitro and in vivo studies, toxicological and ADME (Absorption, Distribution, Metabolism and Excretion) parameters assessments.

Acknowledgements

The Authors thank Nikoletta Szemerédi for her valuable help in the experimental work and Dr. Imre Ocsovszki for the flow cytometry measurements.

Footnotes

  • Authors’ Contributions

    Conceptualization: G.S., E.D.A.; Data curation; B.R., E.K., A.K.; Funding acquisition: G.S., E.D.A.; Investigation: B.R., E.K., A.K.; Methodology: G.S., E.D.A.; Supervision: G.S; Visualization: G.S., E.D.A.; Writing - original draft: B.R., G.S., E.D.A.; Writing - review & editing: B.R., G.S., E.D.A.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    The study was supported by the following organizations and grants: Szeged Foundation for Cancer Research (Szegedi Rákkutatásért Alapítvány), Grant PID2022-136438OB-I00 funded by MCIN/AEI/10.13039/501100011033, European Regional Development Fund - “A way of making Europe” by the European Union. G.S. was supported by the János Bolyai Research Scholarship (BO/00158/22/5) of the Hungarian Academy of Sciences.

  • Received July 21, 2023.
  • Revision received September 12, 2023.
  • Accepted September 13, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
  2. ↵
    1. Kataja V,
    2. Castiglione M
    : Locally recurrent or metastatic breast cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol 19: ii11-ii13, 2008. DOI: 10.1093/annonc/mdn072
    OpenUrlCrossRefPubMed
  3. ↵
    1. Dean M,
    2. Fojo T,
    3. Bates S
    : Tumour stem cells and drug resistance. Nat Rev Cancer 5(4): 275-284, 2005. DOI: 10.1038/nrc1590
    OpenUrlCrossRefPubMed
  4. ↵
    1. Ray PD,
    2. Huang BW,
    3. Tsuji Y
    : Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24(5): 981-990, 2012. DOI: 10.1016/j.cellsig.2012.01.008
    OpenUrlCrossRefPubMed
  5. ↵
    1. Xing F,
    2. Hu Q,
    3. Qin Y,
    4. Xu J,
    5. Zhang B,
    6. Yu X,
    7. Wang W
    : The relationship of redox with hallmarks of cancer: The importance of homeostasis and context. Front Oncol 12: 862743, 2022. DOI: 10.3389/fonc.2022.862743
    OpenUrlCrossRefPubMed
  6. ↵
    1. Gupta SC,
    2. Hevia D,
    3. Patchva S,
    4. Park B,
    5. Koh W,
    6. Aggarwal BB
    : Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 16(11): 1295-1322, 2012. DOI: 10.1089/ars.2011.4414
    OpenUrlCrossRefPubMed
  7. ↵
    1. Ali W,
    2. Álvarez-Pérez M,
    3. Marć MA,
    4. Salardón-Jiménez N,
    5. Handzlik J,
    6. Domínguez-Álvarez E
    : The anticancer and chemopreventive activity of selenocyanate-containing compounds. Curr Pharmacol Rep 4(6): 468-481, 2018. DOI: 10.1007/s40495-018-0160-3
    OpenUrlCrossRef
    1. Avery JC,
    2. Hoffmann PR
    : Selenium, selenoproteins, and immunity. Nutrients 10(9): 1203, 2018. DOI: 10.3390/nu10091203
    OpenUrlCrossRefPubMed
    1. Bartolini D,
    2. Sancineto L,
    3. Fabro de Bem A,
    4. Tew KD,
    5. Santi C,
    6. Radi R,
    7. Toquato P,
    8. Galli F
    : Selenocompounds in cancer therapy: an overview. Adv Cancer Res 136: 259-302, 2017. DOI: 10.1016/bs.acr.2017.07.007
    OpenUrlCrossRefPubMed
    1. Fairweather-Tait SJ,
    2. Bao Y,
    3. Broadley MR,
    4. Collings R,
    5. Ford D,
    6. Hesketh JE,
    7. Hurst R
    : Selenium in human health and disease. Antiox Redox Signal 14(7): 1337-1383, 2011. DOI: 10.1089/ars.2010.3275
    OpenUrlCrossRefPubMed
  11. ↵
    1. Misra S,
    2. Boylan M,
    3. Selvam A,
    4. Spallholz JE,
    5. Björnstedt M
    : Redox-active selenium compounds—from toxicity and cell death to cancer treatment. Nutrients 7(5): 3536-3556, 2015. DOI: 10.3390/nu7053536
    OpenUrlCrossRefPubMed
  12. ↵
    1. Domínguez-Álvarez E,
    2. Rácz B,
    3. Marć MA,
    4. Nasim MJ,
    5. Szemerédi N,
    6. Viktorová J,
    7. Jacob C,
    8. Spengler G
    : Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents. Drug Resist Updat 63: 100844, 2022. DOI: 10.1016/j.drup.2022.100844
    OpenUrlCrossRefPubMed
  13. ↵
    1. Domínguez-Álvarez E,
    2. Spengler G,
    3. Jacob C,
    4. Sanmartín C
    : Selenoester-containing compounds for use in the treatment of microbial infections or colorectal cancer. European Patent EP3628659A1, Sep 28 2018. Available at: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020065086 [Last accessed on September 13, 2023]
  14. ↵
    1. Csonka A,
    2. Kincses A,
    3. Nové M,
    4. Vadas Z,
    5. Sanmartín C,
    6. Domínguez-Álvarez E,
    7. Spengler G
    : Selenoesters and selenoanhydrides as novel agents against resistant breast cancer. Anticancer Res 39(7): 3777-3783, 2019. DOI: 10.21873/anticanres.13526
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Kars MD,
    2. Iseri OD,
    3. Gündüz U,
    4. Ural AU,
    5. Arpaci F,
    6. Molnár J
    : Development of rational in vitro models for drug resistance in breast cancer and modulation of MDR by selected compounds. Anticancer Res 26: 4559-4568, 2006.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Chou T-C
    : Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3): 621-681, 2006. DOI: 10.1124/pr.58.3.10
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Chou T
    : Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2): 440-446, 2010. DOI: 10.1158/0008-5472.CAN-09-1947
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Dongping M,
    2. Cali JJ
    : Identify P-glycoprotein substrates and inhibitors with the rapid, HTS Pgp-Glo™ Assay System. Promega Notes 96: 11-14, 2007.
    OpenUrl
  19. ↵
    1. Rácz B,
    2. Kincses A,
    3. Laczi K,
    4. Rákhely G,
    5. Domínguez-Álvarez E,
    6. Spengler G
    : Reversal of multidrug resistance by symmetrical selenoesters in colon adenocarcinoma cells. Pharmaceutics 15(2): 610, 2023. DOI: 10.3390/pharmaceutics15020610
    OpenUrlCrossRefPubMed
  20. ↵
    1. Mohammad RM,
    2. Muqbil I,
    3. Lowe L,
    4. Yedjou C,
    5. Hsu HY,
    6. Lin LT,
    7. Siegelin MD,
    8. Fimognari C,
    9. Kumar NB,
    10. Dou QP,
    11. Yang H,
    12. Samadi AK,
    13. Russo GL,
    14. Spagnuolo C,
    15. Ray SK,
    16. Chakrabarti M,
    17. Morre JD,
    18. Coley HM,
    19. Honoki K,
    20. Fujii H,
    21. Georgakilas AG,
    22. Amedei A,
    23. Niccolai E,
    24. Amin A,
    25. Ashraf SS,
    26. Helferich WG,
    27. Yang X,
    28. Boosani CS,
    29. Guha G,
    30. Bhakta D,
    31. Ciriolo MR,
    32. Aquilano K,
    33. Chen S,
    34. Mohammed SI,
    35. Keith WN,
    36. Bilsland A,
    37. Halicka D,
    38. Nowsheen S,
    39. Azmi AS
    : Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 35 Suppl(0): S78-S103, 2015. DOI: 10.1016/j.semcancer.2015.03.001
    OpenUrlCrossRefPubMed
  21. ↵
    1. Yuan L,
    2. Cai Y,
    3. Zhang L,
    4. Liu S,
    5. Li P,
    6. Li X
    : Promoting apoptosis, a promising way to treat breast cancer with natural products: a comprehensive review. Front Pharmacol 12: 801662, 2022. DOI: 10.3389/fphar.2021.801662
    OpenUrlCrossRefPubMed
  22. ↵
    1. Zu Y,
    2. Yang Z,
    3. Tang S,
    4. Han Y,
    5. Ma J
    : Effects of P-glycoprotein and its inhibitors on apoptosis in K562 cells. Molecules 19(9): 13061-13075, 2014. DOI: 10.3390/molecules190913061
    OpenUrlCrossRefPubMed
  23. ↵
    1. Gopisetty MK,
    2. Kovács D,
    3. Igaz N,
    4. Rónavári A,
    5. Bélteky P,
    6. Rázga Z,
    7. Venglovecz V,
    8. Csoboz B,
    9. Boros IM,
    10. Kónya Z,
    11. Kiricsi M
    : Endoplasmic reticulum stress: major player in size-dependent inhibition of P-glycoprotein by silver nanoparticles in multidrug-resistant breast cancer cells. J Nanobiotechnology 17(1): 9, 2019. DOI: 10.1186/s12951-019-0448-4
    OpenUrlCrossRefPubMed
  24. ↵
    1. Seiler N,
    2. Raul F
    : Polyamines and apoptosis. J Cell Mol Med 9(3): 623-642, 2005. DOI: 10.1111/j.1582-4934.2005.tb00493.x
    OpenUrlCrossRefPubMed
  25. ↵
    1. Álvarez-Pérez M,
    2. Ali W,
    3. Marć MA,
    4. Handzlik J,
    5. Domínguez-Álvarez E
    : Selenides and diselenides: a review of their anticancer and chemopreventive activity. Molecules 23(3): 628, 2018. DOI: 10.3390/molecules23030628
    OpenUrlCrossRefPubMed
  26. ↵
    1. Sanmartín C,
    2. Font M,
    3. Palop J
    : Molecular symmetry: a structural property frequently present in new cytotoxic and proapoptotic drugs. Mini Rev Med Chem 6(6): 639-650, 2006. DOI: 10.2174/138955706777435652
    OpenUrlCrossRefPubMed
  27. ↵
    1. Ibáñez E,
    2. Plano D,
    3. Font M,
    4. Calvo A,
    5. Prior C,
    6. Palop JA,
    7. Sanmartín C
    : Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates. Eur J Med Chem 46(1): 265-274, 2011. DOI: 10.1016/j.ejmech.2010.11.013
    OpenUrlCrossRefPubMed
  28. ↵
    1. Lagunes I,
    2. Begines P,
    3. Silva A,
    4. Galán AR,
    5. Puerta A,
    6. Fernandes MX,
    7. Maya I,
    8. Fernández-Bolaños JG,
    9. López Ó,
    10. Padrón JM
    : Selenocoumarins as new multitarget antiproliferative agents: Synthesis, biological evaluation and in silico calculations. Eur J Med Chem 179: 493-501, 2019. DOI: 10.1016/j.ejmech.2019.06.073
    OpenUrlCrossRefPubMed
  29. ↵
    1. Nové M,
    2. Kincses A,
    3. Szalontai B,
    4. Rácz B,
    5. Blair JMA,
    6. González-Prádena A,
    7. Benito-Lama M,
    8. Domínguez-Álvarez E,
    9. Spengler G
    : Biofilm eradication by symmetrical selenoesters for food-borne pathogens. Microorganisms 8(4): 566, 2020. DOI: 10.3390/microorganisms8040566
    OpenUrlCrossRefPubMed
  30. ↵
    1. De la Cruz-Claure ML,
    2. Cèspedes-Llave AA,
    3. Ulloa MT,
    4. Benito-Lama M,
    5. Domínguez-Álvarez E,
    6. Bastida A
    : Inhibition-Disruption of Candida glabrata biofilms: Symmetrical selenoesters as potential anti-biofilm agents. Microorganisms 7(12): 664, 2019. DOI: 10.3390/microorganisms7120664
    OpenUrlCrossRefPubMed
  31. ↵
    1. Gajdács M,
    2. Spengler G,
    3. Sanmartín C,
    4. Marć MA,
    5. Handzlik J,
    6. Domínguez-Álvarez E
    : Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line. Bioorg Med Chem Lett 27(4): 797-802, 2017. DOI: 10.1016/j.bmcl.2017.01.033
    OpenUrlCrossRefPubMed
  32. ↵
    1. Li A,
    2. Song NJ,
    3. Riesenberg BP,
    4. Li Z
    : The emerging roles of endoplasmic reticulum stress in balancing immunity and tolerance in health and diseases: mechanisms and opportunities. Front Immunol 10: 3154, 2020. DOI: 10.3389/fimmu.2019.03154
    OpenUrlCrossRefPubMed
  33. ↵
    1. Li J,
    2. Meng Y,
    3. Wu X,
    4. Sun Y
    : Polyamines and related signaling pathways in cancer. Cancer Cell Int 20(1): 539, 2020. DOI: 10.1186/s12935-020-01545-9
    OpenUrlCrossRef
    1. Sancha SAR,
    2. Szemerédi N,
    3. Spengler G,
    4. Ferreira MU
    : Lycorine carbamate derivatives for reversing P-glycoprotein-mediated multidrug resistance in human colon adenocarcinoma cells. Int J Mol Sci 24(3): 2061, 2023. DOI: 10.3390/ijms24032061
    OpenUrlCrossRefPubMed
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Antitumor Activity of Symmetrical Selenoesters in Doxorubicin Resistant Breast Cancer
BALINT RACZ, ERZSEBET KRISTOF, ANNAMARIA KINCSES, ENRIQUE DOMINGUEZ-ALVAREZ, GABRIELLA SPENGLER
Anticancer Research Nov 2023, 43 (11) 4865-4872; DOI: 10.21873/anticanres.16683
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