The role of autophagy in the mechanisms of tumor cell chemoresistance induced by anthracycline antibiotic use

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Abstract

Autophagy is not just a way to get rid of damaged, mutated, or genetically unstable cells, but it also increases the chances that tumor cells can overcome the effects of chemotherapy-induced damage. Anthracyclines have a cytoprotective effect of autophagy in most cancer cell lines. The blocking of autophagy in this case makes tumor cells more sensitive to therapy. Cytoprotective autophagy activation can cause chemoresistance, and if it is overstimulated, it can cause energy depletion and autophagic death. In some cases, cytotoxic autophagy develops under the action of anthracyclines and blocking it increases cell survival. On the contrary, activation of cytotoxic autophagy triggers the process of "self-eating". Modulating autophagy can be a dual-edged sword for tumor cells, leading to both death and survival.

About the authors

N. A. Persiyantseva

N. N. Blokhin National Medical Research Center of Oncology

Author for correspondence.
Email: nadushka99@gmail.com
Moscow

E. S. Ivanova

N. N. Blokhin National Medical Research Center of Oncology; Institute of Cyber Intelligence Systems, National Research Nuclear University MEPHI

Email: nadushka99@gmail.com
Moscow; Moscow

M. A. Zamkova

N. N. Blokhin National Medical Research Center of Oncology; Institute of Cyber Intelligence Systems, National Research Nuclear University MEPHI

Email: nadushka99@gmail.com
Moscow; Moscow

References

  1. Li, X., He, S., and Ma, B. (2020) Autophagy and autophagy-related proteins in cancer, Mol. Cancer, 19, 12, https://doi.org/10.1186/s12943-020-1138-4.
  2. Mizushima, N., and Komatsu, M. (2011) Autophagy: renovation of cells and tissues, Cell, 147, 728-741, https://doi.org/10.1016/j.cell.2011.10.026.
  3. Swedan, H. K., Kassab, A. E., Gedawy, E. M., and Elmeligie, S. E. (2023) Topoisomerase II inhibitors design: early studies and new perspectives, Bioorg. Chem., 136, 106548, https://doi.org/10.1016/j.bioorg.2023.106548.
  4. Kciuk, M., Gielecińska, A., Mujwar, S., Kołat, D., Kałuzińska-Kołat, Ż., Celik, I., and Kontek, R. (2023) Doxorubicin – an agent with multiple mechanisms of anticancer activity, Cells, 12, 659, https://doi.org/10.3390/cells12040659.
  5. Al-Aamri, H. M., Ku, H., Irving, H. R., Tucci, J., Meehan-Andrews, T., and Bradley, C. (2019) Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia, BMC Cancer, 19, 179, https://doi.org/10.1186/s12885-019-5377-y.
  6. Qiu, L., Zhou, G., and Cao, S. (2020) Targeted inhibition of ULK1 enhances daunorubicin sensitivity in acute myeloid leukemia, Life Sci., 243, 117234, https://doi.org/10.1016/j.lfs.2019.117234.
  7. Tan, Q., Wang, H., Hu, Y., Hu, M., Li, X., Aodengqimuge, Ma, Y., Wei, C., and Song, L. (2015) Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy, Cancer Sci., 106, 1023-1032, https://doi.org/10.1111/cas.12712.
  8. Han, Y., Fan, S., Qin, T., Yang, J., Sun, Y., Lu, Y., Mao, J., and Li, L. (2018) Role of autophagy in breast cancer and breast cancer stem cells, Int. J. Oncol., 52, 1057-1070, https://doi.org/10.3892/ijo.2018.4270.
  9. Dudkowska, M., Staniak, K., Bojko, A., and Sikora, E. (2021) The role of autophagy in escaping therapy-induced polyploidy/senescence, Adv. Cancer Res., 150, 209-247, https://doi.org/10.1016/bs.acr.2021.01.004.
  10. Chude, C. I., and Amaravadi, R. K. (2017) Targeting autophagy in cancer: update on clinical trials and novel inhibitors, Int. J. Mol. Sci., 18, 1279, https://doi.org/10.3390/ijms18061279.
  11. Shi, Y., Lin, G., Zheng, H., Mu, D., Chen, H., Lu, Z., He, P., Zhang, Y., Liu, C., Lin, Z., and Liu, G. (2021) Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly, J. Nanobiotechnology, 19, 447, https://doi.org/10.1186/s12951-021-01189-5.
  12. Chang, H., and Zou, Z. (2020) Targeting autophagy to overcome drug resistance: further developments, J. Hematol. Oncol., 13, 159, https://doi.org/10.1186/s13045-020-01000-2.
  13. Meredith, A. M., and Dass, C. R. (2016) Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism, J. Pharm. Pharmacol., 68, 729-741, https://doi.org/10.1111/jphp.12539.
  14. Skok, Ž., Zidar, N., Kikelj, D., and Ilaš, J. (2020) Dual inhibitors of human DNA topoisomerase II and other cancer-related targets, J. Med. Chem., 63, 884-904, https://doi.org/10.1021/acs.jmedchem.9b00726.
  15. Hurvitz, S. A., McAndrew, N. P., Bardia, A., Press, M. F., Pegram, M., Crown, J. P., Fasching, P. A., Ejlertsen, B., Yang, E. H., Glaspy, J. A., and Slamon, D. J. (2021) A careful reassessment of anthracycline use in curable breast cancer, Breast Cancer, 7, 134, https://doi.org/10.1038/s41523-021-00342-5.
  16. Corremans, R., Adão, R., De Keulenaer, G. W., Leite-Moreira, A. F., and Brás-Silva, C. (2019) Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity, Clin. Exp. Pharmacol. Physiol., 46, 204-215, https://doi.org/10.1111/1440-1681.13036.
  17. Varela-López, A., Battino, M., Navarro-Hortal, M. D., Giampieri, F., Forbes-Hernández, T. Y., Romero-Márquez, J. M., Collado, R., and Quiles, J. L. (2019) An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients, Food Chem. Toxicol., 134, 110834, https://doi.org/10.1016/j.fct.2019.110834.
  18. Papazoglou, P., Peng, L., and Sachinidis, A. (2021) Epigenetic mechanisms involved in the cardiovascular toxicity of anticancer drugs, Front. Cardiovasc. Med., 8, 658900, https://doi.org/10.3389/fcvm.2021.658900.
  19. Mosieniak, G., Sliwinska, M. A., Alster, O., Strzeszewska, A., Sunderland, P., Piechota, M., Was, H., and Sikora, E. (2015) Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence, Neoplasia, 17, 882-893, https://doi.org/10.1016/j.neo.2015.11.008.
  20. Guo, W., Wang, Y., Wang, Z., Wang, Y. P., and Zheng, H. (2016) Inhibiting autophagy increases epirubicin’s cytotoxicity in breast cancer cells, Cancer Sci., 107, 1610-1621, https://doi.org/10.1111/cas.13059.
  21. Akar, U., Chaves-Reyez, A., Barria, M., Tari, A., Sanguino, A., Kondo, Y., Kondo, S., Arun, B., Lopez-Berestein, G., and Ozpolat, B. (2008) Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells, Autophagy, 4, 669-679, https://doi.org/10.4161/auto.6083.
  22. Ji, C., Yang, B., Yang, Y. L., He, S. H., Miao, D. S., He, L., and Bi, Z. G. (2010) Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition, Oncogene, 29, 6557-6568, https://doi.org/10.1038/onc.2010.379.
  23. Giorgi, C., Bonora, M., Sorrentino, G., Missiroli, S., Poletti, F., Suski, J. M., Galindo Ramirez, F., Rizzuto, R., Di Virgilio, F., Zito, E., Pandolfi, P. P., Wieckowski, M. R., Mammano, F., Del Sal, G., and Pinton, P. (2015) P53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner, Proc. Natl. Acad. Sci. USA, 112, 1779-1784, https://doi.org/10.1073/pnas.1410723112.
  24. Yamamoto, H., and Matsui, T. (2024) Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy, J. Nippon Med. Sch., 91, 2-9, https://doi.org/10.1272/jnms.JNMS.2024_91-102.
  25. Fan, X., He, Y., Wu, G., Chen, H., Cheng, X., Zhan, Y., An, C., Chen, T., and Wang, X. (2023) Sirt3 activates autophagy to prevent DOX-induced senescence by inactivating PI3K/AKT/mTOR pathway in A549 cells, Biochim. Biophys. Acta Mol. Cell Res., 1870, 19411, https://doi.org/10.1016/j.bbamcr.2022.119411.
  26. Ahmadi-Dehlaghi, F., Mohammadi, P., Valipour, E., Pournaghi, P., Kiani, S., and Mansouri, K. (2023) Autophagy: A challengeable paradox in cancer treatment, Cancer Med., 12, 11542-11569, https://doi.org/10.1002/cam4.5577.
  27. Kim, J., Kundu, M., Viollet, B., and Guan, K. L. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1, Nat. Cell Biol., 13, 132-141, https://doi.org/10.1038/ncb2152.
  28. Barth, S., Glick, D., and Macleod, K. F. (2010) Autophagy: assays and artifacts, J. Patholog., 221, 117-124, https://doi.org/10.1002/path.2694.
  29. Li, J., Zhou, W., Mao, Q., Gao, D., Xiong, L., Hu, X., Zheng, Y., and Xu, X. (2021) HMGB1 promotes resistance to doxorubicin in human hepatocellular carcinoma cells by inducing autophagy via the AMPK/mTOR signaling pathway, Front. Oncol., 11, 739145, https://doi.org/10.3389/fonc.2021.739145.
  30. Romaniuk-Drapała, A., Totoń, E., Konieczna, N., Machnik, M., Barczak, W., Kowal, D., Kopczyński, P., Kaczmarek, M., and Rubiś, B. (2021) hTERT downregulation attenuates resistance to DOX, impairs FAK-mediated adhesion, and leads to autophagy induction in breast cancer cells, Cells, 10, 867, https://doi.org/10.3390/cells10040867.
  31. Rogov, V., Dötsch, V., Johansen, T., and Kirkin, V. (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy, Mol. Cell, 53, 1934-1951, https://doi.org/10.1016/j.molcel.2013.12.014.
  32. Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J. A., Outzen, H., Øvervatn, A., Bjørkøy, G., and Johansen, T. (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy, J. Biol. Chem., 282, 24131-24145, https://doi.org/10.1074/jbc.M702824200.
  33. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., and Johansen, T. (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death, J. Cell Biol., 171, 603-614, https://doi.org/10.1083/jcb.200507002.
  34. Wang, H., Cheng, Q., Bao, L., Li, M., Chang, K., and Yi, X. (2023) Cytoprotective role of heme oxygenase-1 in cancer chemoresistance: focus on antioxidant, antiapoptotic, and pro-autophagy properties, Antioxidants, 12, 1217, https://doi.org/10.3390/antiox12061217.
  35. Yan, C., Luo, L., Guo, C. Y., Goto, S., Urata, Y., Shao, J. H., and Li, T. S. (2017) Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells, Cancer Lett., 388, 34-42, https://doi.org/10.1016/j.canlet.2016.11.018.
  36. Jacquet, M., Guittaut, M., Fraichard, A., and Despouy, G. (2021) The functions of Atg8-family proteins in autophagy and cancer: linked or unrelated? Autophagy, 17, 599-611, https://doi.org/10.1080/15548627.2020.1749367.
  37. Naso, F. D., Bruqi, K., Manzini, V., Chiurchiù, V., D’Onofrio, M., Arisi, I., and Strappazzon, F. (2024) miR-218-5p and doxorubicin combination enhances anticancer activity in breast cancer cells through Parkin-dependent mitophagy inhibition, Cell Death Discov., 10, 149, https://doi.org/10.1038/s41420-024-01914-7.
  38. Zhou, J., Li, G., Zheng, Y., Shen, H. M., Hu, X., Ming, Q. L., Huang, C., Li, P., and Gao, N. (2015) A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission, Autophagy, 11, 1259-1279, https://doi.org/10.1080/15548627.2015.1056970.
  39. Yao, J., Wang, J., Xu, Y., Guo, Q., Sun, Y., Liu, J., Li, S., Guo, Y., and Wei, L. (2022) CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma, Autophagy, 18, 1879-1897, https://doi.org/10.1080/15548627.2021.2007027.
  40. Bong, A. H. L., Bassett, J. J., Roberts-Thomson, S. J., and Monteith, G. R. (2020) Assessment of doxorubicin-induced remodeling of Ca2+ signaling and associated Ca2+ regulating proteins in MDA-MB-231 breast cancer cells, Biochem. Biophys. Res. Commun., 522, 532-538, https://doi.org/10.1016/j.bbrc.2019.11.136.
  41. Peters, A. A., Milevskiy, M. J., Lee, W. C., Curry, M. C., Smart, C. E., Saunus, J. M., Reid, L., da Silva, L., Marcial, D. L., Dray, E., Brown, M. A., Lakhani, S. R., Roberts-Thomson, S. J., and Monteith, G. R. (2016) The calcium pump plasma membrane Ca2+-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin, Sci. Rep., 6, 25505, https://doi.org/10.1038/srep25505.
  42. Zhang, P., Liu, X., Li, H., Chen, Z., Yao, X., Jin, J., and Ma, X. (2017) TRPC5-induced autophagy promotes drug resistance in breast carcinoma via CaMKKβ/AMPKα/mTOR pathway, Sci. Rep., 7, 3158, https://doi.org/10.1038/s41598-017-03230-w.
  43. Paquette, M., El-Houjeiri, L., Zirden, L. C., Puustinen, P., Blanchette, P., Jeong, H., Dejgaard, K., Siegel, P. M., and Pause, A. (2021) AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3, Autophagy, 17, 3957-3975, https://doi.org/10.1080/15548627.2021.1898748.
  44. Slade, L., Biswas, D., Ihionu, F., El Hiani, Y., Kienesberger, P. C., and Pulinilkunnil, T. (2020) A lysosome independent role for TFEB in activating DNA repair and inhibiting apoptosis in breast cancer cells, Biochem. J., 477, 137-160, https://doi.org/10.1042/BCJ20190596.
  45. Pisonero-Vaquero, S., Soldati, C., Cesana, M., Ballabio, A., and Medina, D. L. (2020) TFEB modulates p21/WAF1/CIP1 during the DNA damage response, Cells, 9, 1186, https://doi.org/10.3390/cells9051186.
  46. Yamashita, G., Takano, N., Kazama, H., Tsukahara, K., and Miyazawa, K. (2022) p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs, Cell Death Discov., 8, 502, https://doi.org/10.1038/s41420-022-01293-x.
  47. Fang, L. M., Li, B., Guan, J. J., Xu, H. D., Shen, G. H., Gao, Q. G., and Qin, Z. H. (2017) Transcription factor EB is involved in autophagy-mediated chemoresistance to doxorubicin in human cancer cells, Acta Pharmacol. Sin., 38, 1305-1316, https://doi.org/10.1038/aps.2017.25.
  48. Gomes, L. R., Vessoni, A. T., and Menck, C. F. M. (2015) Three-dimensional microenvironment confers enhanced sensitivity to doxorubicin by reducing p53-dependent induction of autophagy, Oncogene, 34, 5329-5340, https://doi.org/10.1038/onc.2014.461.
  49. Yousefi, S., Perozzo, R., Schmid, I., Ziemiecki, A., Schaffner, T., Scapozza, L., Brunner, T., and Simon, H. U. (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis, Nat. Cell Biol., 8, 1124-1132, https://doi.org/10.1038/ncb1482.
  50. Zhou, Z., Xu, S., Jiang, L., Tan, Z., and Wang, J. (2022) A systematic pan-cancer analysis of CASP3 as a potential target for immunotherapy, Front. Mol. Biosci., 9, 776808, https://doi.org/10.3389/fmolb.2022.776808.
  51. Bollaert, E., Claus, M., Vandewalle, V., Lenglez, S., Essaghir, A., Demoulin, J. B., and Havelange, V. (2021) Mir-15a-5p confers chemoresistance in acute myeloid leukemia by inhibiting autophagy induced by daunorubicin, Int. J. Mol. Sci., 22, 5153, https://doi.org/10.3390/ijms22105153.
  52. Manov, I., Pollak, Y., Broneshter, R., and Iancu, T. C. (2011) Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by sorafenib – the role of extracellular signal-regulated kinase counteraction, FEBS J., 278, 3494-3507, https://doi.org/10.1111/j.1742-4658.2011.08271.x.
  53. Eng, C. H., Wang, Z., Tkach, D., Toral-Barza, L., Ugwonali, S., Liu, S., Fitzgerald, S. L., George, E., Frias, E., Cochran, N., De Jesus, R., McAllister, G., Hoffman, G. R., Bray, K., Lemon, L., Lucas, J., Fantin, V. R., Abraham, R. T., Murphy, L. O., and Nyfeler, B. (2016) Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy, Proc. Natl. Acad. Sci. USA, 113, 182-187, https://doi.org/10.1073/pnas.1515617113.
  54. Saleh, T., Tyutyunyk-Massey, L., Patel, N. H., Cudjoe, E. K., Jr., Alotaibi, M., and Gewirtz, D. A. (2020) Studies of non-protective autophagy provide evidence that recovery from therapy-induced senescence is independent of early autophagy, Int. J. Mol. Sci., 21, 1427, https://doi.org/10.3390/ijms21041427.
  55. Lucianò, A. M., Pérez-Oliva, A. B., Mulero, V., and Del Bufalo, D. (2021) Bcl-xL: a focus on melanoma pathobiology, Int. J. Mol. Sci., 22, 2777, https://doi.org/10.3390/ijms22052777.
  56. Chen, C., Zhou, Y., Ding, P., and He, L. (2021) MiR-1 targeted downregulation of Bcl-2 increases chemosensitivity of lung cancer cells, Genet. Test Mol. Biomarkers, 25, 540-545, https://doi.org/10.1089/gtmb.2021.0009.
  57. Xiang, H., Liu, R., Zhang, X., An, R., Zhou, M., Tan, C., Li, Q., Su, M., Guo, C., Zhou, L., Li, Y., and Wang, R. (2023) Discovery of small-molecule autophagy inhibitors by disrupting the protein-protein interactions involving autophagy-related 5, J. Med. Chem., 66, 2457-2476, https://doi.org/10.1021/acs.jmedchem.2c01233.
  58. Liang, A. L., Zhang, J., Du, S. L., Zhang, B., Ma, X., Wu, C. Y., and Liu, Y. J. (2020) Chloroquine increases the anti-cancer activity of epirubicin in A549 lung cancer cells, Oncol. Lett., 20, 53-60, https://doi.org/10.3892/ol.2020.11567.
  59. Guo, B., Tam, A., Santi, S. A., and Parissenti, A. M. (2016) Role of autophagy and lysosomal drug sequestration in acquired resistance to doxorubicin in MCF-7 cells, BMC Cancer, 16, 762, https://doi.org/10.1186/s12885-016-2790-3.
  60. Garbar, C., Mascaux, C., Giustiniani, J., Merrouche, Y., and Bensussan, A. (2017) Chemotherapy treatment induces an increase of autophagy in the luminal breast cancer cell MCF7, but not in the triple-negative MDA-MB231, Sci. Rep., 7, 7201, https://doi.org/10.1038/s41598-017-07489-x.
  61. Loh, J. S., Rahim, N. A., Tor, Y. S., and Foo, J. B. (2022) Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells, Cell Biochem. Funct., 40, 403-416, https://doi.org/10.1002/cbf.3704.
  62. Yu, L., Shi, Q., Jin, Y., Liu, Z., Li, J., and Sun, W. (2021) Blockage of AMPK-ULK1 pathway mediated autophagy promotes cell apoptosis to increase doxorubicin sensitivity in breast cancer (BC) cells: an in vitro study, BMC Cancer, 21, 195, https://doi.org/10.1186/s12885-021-07901-w.
  63. Kim, D. G., Jung, K. H., Lee, D. G., Yoon, J. H., Choi, K. S., Kwon, S. W., Shen, H. M., Morgan, M. J., Hong, S. S., and Kim, Y. S. (2014) 20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin, Oncotarget, 5, 4438-4451, https://doi.org/10.18632/oncotarget.2034.
  64. Was, H., Barszcz, K., Czarnecka, J., Kowalczyk, A., Bernas, T., Uzarowska, E., Koza, P., Klejman, A., Piwocka, K., Kaminska, B., and Sikora, E. (2017) Bafilomycin A1 triggers proliferative potential of senescent cancer cells in vitro and in NOD/SCID mice, Oncotarget, 8, 9303-9322, https://doi.org/10.18632/oncotarget.14066.
  65. Chen, H., Zhao, C., He, R., Zhou, M., Liu, Y., Guo, X., Wang, M., Zhu, F., Qin, R., and Li, X. (2019) Danthron suppresses autophagy and sensitizes pancreatic cancer cells to doxorubicin, Toxicol. in Vitro, 54, 345-353, https://doi.org/10.1016/j.tiv.2018.10.019.
  66. Zhao, D., Yuan, H., Yi, F., Meng, C., and Zhu, Q. (2014) Autophagy prevents doxorubicin-induced apoptosis in osteosarcoma, Mol. Med. Rep., 9, 1975-1981, https://doi.org/10.3892/mmr.2014.2055.
  67. Zhou, Y., Chen, E., Tang, Y., Mao, J., Shen, J., Zheng, X., Xie, S., Zhang, S., Wu, Y., Liu, H., Zhi, X., Ma, T., Ni, H., Chen, J., Chai, K., and Chen, W. (2019) miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells, Cell Death Dis., 10, 843, https://doi.org/10.1038/s41419-019-2053-8.
  68. Melles, R. B., Jorge, A. M., Marmor, M. F., Zhou, B., Conell, C., Niu, J., McCormick, N., Zhang, Y., and Choi, H. K. (2023) Hydroxychloroquine dose and risk for incident retinopathy: a cohort study, Ann. Intern. Med., 176, 166-173, https://doi.org/10.7326/M22-2453.
  69. Gupta, G., Borglum, K., and Chen, H. (2021) Immunogenic cell death: a step ahead of autophagy in cancer therapy, J. Cancer Immunol., 3, 47-59, https://doi.org/10.33696/cancerimmunol.3.041.
  70. Vargas, J. E., Puga, R., Lenz, G., Trindade, C., and Filippi-Chiela, E. (2020) Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: a translational in vitro-in silico model, Oxid. Med. Cell Longev., 2020, 5432651, https://doi.org/10.1155/2020/5432651.
  71. Liu, Z., Shi, A., Song, D., Han, B., Zhang, Z., Ma, L., Liu, D., and Fan, Z. (2017) Resistin confers resistance to doxorubicin-induced apoptosis in human breast cancer cells through autophagy induction, Am. J. Cancer Res., 7, 574-583.
  72. Settembre, C., Zoncu, R., Medina, D. L., Vetrini, F., Erdin, S., Erdin, S., Huynh, T., Ferron, M., Karsenty, G., Vellard, M. C., Facchinetti, V., Sabatini, D. M., and Ballabio, A. (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB, EMBO J., 31, 1095-1108, https://doi.org/10.1038/emboj.2012.32.
  73. Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M. K., Ferrone, C. R., Settleman, J., Stephanopoulos, G., Dyson, N. J., Zoncu, R., Ramaswamy, S., Haas, W., and Bardeesy, N. (2015) Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism, Nature, 524, 361-365, https://doi.org/10.1038/nature14587.
  74. Hseu, Y. C., Lin, R. W., Shen, Y. C., Lin, K. Y., Liao, J. W., Thiyagarajan, V., and Yang, H. L. (2020) Flavokawain b and doxorubicin work synergistically to impede the propagation of gastric cancer cells via ROS-mediated apoptosis and autophagy pathways, Cancers (Basel), 12, 2475, https://doi.org/10.3390/cancers12092475.
  75. Fong, M. Y., Jin, S., Rane, M., Singh, R. K., Gupta, R., and Kakar, S. S. (2012) Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer, PLoS One, 7, e42265, https://doi.org/10.1371/journal.pone.0042265.
  76. Li, J. (2023) Chidamide enhances cytotoxicity of doxorubicin by promoting autophagy and apoptosis in breast cancer, BMC Cancer, 23, 353, https://doi.org/10.1186/s12885-023-10774-w.
  77. Zhang, M., Zhang, H., Tang, F., Wang, Y., Mo, Z., Lei, X., and Tang, S. (2016) Doxorubicin resistance mediated by cytoplasmic macrophage colony-stimulating factor is associated with switch from apoptosis to autophagic cell death in MCF-7 breast cancer cells, Exp. Biol. Med., 241, 2086-2093, https://doi.org/10.1177/1535370216660399.
  78. Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., Mendoza-Parra, M. A., Kanashova, T., Metzner, M., Pardon, K., Reimann, M., Trumpp, A., Dörken, B., Zuber, J., Gronemeyer, H., Hummel, M., Dittmar, G., Lee S., and Schmitt, C. A. (2018) Senescence-associated reprogramming promotes cancer stemness, Nature, 553, 96-100, https://doi.org/10.1038/nature25167.
  79. Zamkova, M. A., Persiyantseva, N. A., Tatarskiy, V. V., and Shtil, A. A. (2023) Therapy-induced tumor cell senescence: mechanisms and circumvention, Biochemistry (Moscow), 88, 86-104, https://doi.org/10.1134/S000629792301008X.
  80. Cassidy, L. D., and Narita, M. (2022) Autophagy at the intersection of aging, senescence, and cancer, Mol. Oncol., 16, 3259-3275, https://doi.org/10.1002/1878-0261.13269.
  81. Yang, M. Y., Lin, P. M., Liu, Y. C., Hsiao, H. H., Yang, W. C., Hsu, J. F., Hsu, C. M., and Lin, S. F. (2012) Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells, PLoS One, 7, e37205, https://doi.org/10.1371/journal.pone.0037205.
  82. Bojko, A., Czarnecka-Herok, J., Charzynska, A., Dabrowski, M., and Sikora, E. (2019) Diversity of the senescence phenotype of cancer cells treated with chemotherapeutic agents, Cells, 8, 1501, https://doi.org/10.3390/cells8121501.
  83. Abdelmoaty, A. A. A., Chen, J., Zhang, K., Wu, C., Li, Y., Li, P., and Xu, J. (2024) Senolytic effect of triterpenoid complex from Ganoderma lucidum on adriamycin-induced senescent human hepatocellular carcinoma cells model in vitro and in vivo, Front. Pharmacol., 15, 1422363, https://doi.org/10.3389/fphar.2024.1422363.
  84. Filippi-Chiela, E. C., Silva, M. M. B., Thomé, M. P., and Lenz, G. (2015) Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage, Autophagy, 11, 1099-1113, https://doi.org/10.1080/15548627.2015.1009795.
  85. Goehe, R. W., Di, X., Sharma, K., Bristol, M. L., Henderson, S. C., Valerie, K., Rodier, F., Davalos, A. R., and Gewirtz, D. A. (2012) The autophagy-senescence connection in chemotherapy: must tumor cells (self) eat before they sleep, J. Pharmacol. Exp. Ther., 343, 763-778, https://doi.org/10.1124/jpet.112.197590.
  86. Aqbi, H. F., Tyutyunyk-Massey, L., Keim, R. C., Butler, S. E., Thekkudan, T., Joshi, S., Smith, T. M., Bandyopadhyay, D., Idowu, M. O., Bear, H. D., Payne, K. K., Gewirtz, D. A., and Manjili, M. H. (2018) Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy, Oncotarget, 9, 22113-22122, https://doi.org/10.18632/oncotarget.25197.
  87. Wang, L., Yao, L., Zheng, Y. Z., Xu, Q., Liu, X. P., Hu, X., Wang, P., and Shao, Z. M. (2015) Expression of autophagy-related proteins ATG5 and FIP200 predicts favorable disease-free survival in patients with breast cancer, Biochem. Biophys. Res. Commun., 458, 816-822, https://doi.org/10.1016/j.bbrc.2015.02.037.
  88. Takasugi, M., Yoshida, Y., and Ohtani, N. (2022) Cellular senescence and the tumour microenvironment, Mol. Oncol., 16, 3333-3351, https://doi.org/10.1002/1878-0261.13268.
  89. Payea, M. J., Anerillas, C., Tharakan, R., and Gorospe, M. (2021) Translational control during cellular senescence, Mol. Cell Biol., 41, e00512-20, https://doi.org/10.1128/MCB.00512-20.
  90. Skrzeszewski, M., Maciejewska, M., Kobza, D., Gawrylak, A., Kieda, C., and Waś, H. (2024) Risk factors of using late-autophagy inhibitors: aspects to consider when combined with anticancer therapies, Biochem. Pharmacol., 225, 116277, https://doi.org/10.1016/j.bcp.2024.116277
  91. Guo, H., Zhu, Q., Yu, X., Merugu, S. B., Mangukiya, H. B., Smith, N., Li, Z., Zhang, B., Negi, H., Rong, R., Cheng, K., Wu, Z., and Li, D. (2017) Tumor-secreted anterior gradient-2 binds to VEGF and FGF2 and enhances their activities by promoting their homodimerization, Oncogene, 36, 5098-5109, https://doi.org/10.1038/onc.2017.132.
  92. Maarouf, A., Boissard, A., Henry, C., Leman, G., Coqueret, O., Guette, C., and Lelièvre, E. (2022) Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy-induced senescence escape, Int. J. Oncol., 60, 5, https://doi.org/10.3892/ijo.2021.5295.

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