The Premature Senescence in Breast Cancer Treatment Strategy
Abstract
:1. Introduction
1.1. Breast Cancer Treatment Strategy
1.2. Cellular Senescence
2. Senescence and Anticancer Strategy
2.1. Chemotherapy and Senescence Induction
2.1.1. Topoisomerase Inhibitors
2.1.2. Antimetabolites
2.1.3. Microtubule Targeting Agents
2.1.4. Platinum-Based Anticancer Drugs
2.2. Other Drugs
2.2.1. Poly(ADP-Ribose) Polymerase 1 Inhibitors (PARPis)
2.2.2. Antiestrogenic Therapy
2.2.3. HER2-Targeted Tyrosine Kinase Inhibitors
3. Senescence in Clinical Trials or Clinical Practice
4. Senescence Induction as a New Anticancer Strategy
4.1. Inhibitors of Aurora A
4.2. Nanoparticle-Based Drug Delivery Systems
4.3. Natural Compound-Induced Senescence in Breast Cancer Cells
4.3.1. ROS Production as the Mechanism of Senescence
4.3.2. DNA Damage Inductors
4.3.3. Epigenetic Modulators
4.3.4. Hampering Overexpressed Pathways
5. Prevention of SASP in Breast Cancer Studies
5.1. Senostatics and Breast Cancer Studies
5.2. Senolytics and Breast Cancer Studies
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perou, C.M.; Sørile, T.; Eisen, M.B.; Van De Rijn, M.; Jeffrey, S.S.; Ress, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef]
- Therese Sørliea, B.C.; Charles, M.; Peroua, D.; Robert, T.; Turid, A.; Stephanie, G.; Hilde, J.; Trevor, H.; Michael, B.; Eisenh, M.; et al. Departments Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 2001, 98, 10869–10874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kondov, B.; Milenkovikj, Z.; Kondov, G.; Petrushevska, G.; Basheska, N.; Bogdanovska-Todorovska, M.; Tolevska, N.; Ivkovski, L. Presentation of the molecular subtypes of breast cancer detected by immunohistochemistry in surgically treated patients. Open Access Maced. J. Med. Sci. 2018, 6, 961–967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Darby, S.; McGale, P.; Correa, C.; Taylor, C.; Arriagada, R.; Clarke, M.; Cutter, D.; Davies, C.; Ewertz, M.; Godwin, J.; et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011, 378, 1707–1716. [Google Scholar] [PubMed] [Green Version]
- Waks, A.G.; Winer, E.P. Breast Cancer Treatment: A Review. J. Am. Med. Assoc. 2019, 321, 288–300. [Google Scholar] [CrossRef]
- Harbeck, N.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast Cancer. Nat. Rev. Dis. Prim. 2016, 5, 66. [Google Scholar] [CrossRef]
- Muñoz-Espín, D.; Serrano, M. Cellular senescence: From physiology to pathology. Nat. Rev. Mol. Cell Biol. 2014, 15, 482–496. [Google Scholar] [CrossRef]
- Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 1965, 636, 614–636. [Google Scholar] [CrossRef]
- Calvin, B.; Harley, A.; Bruce Futcher, C.W.G. Telomeres shorten during ageing of human fibroloblasts. Nature 1990, 345, 458–460. [Google Scholar]
- Kuilman, T.; Michaloglou, C.; Mooi, W.J.; Peeper, D.S. The essence of senescence. Gen. Dev. 2010, 24, 2463–2479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mikuła-Pietrasik, J.; Niklas, A.; Uruski, P.; Tykarski, A.; Książek, K. Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells. Cell. Mol. Life Sci. 2019, 77, 213–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. Mech. Dis. 2010, 5, 99–118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Faget, D.V.; Ren, Q.; Stewart, S.A. Unmasking senescence: Context-dependent effects of SASP in cancer. Nat. Rev. Cancer 2019, 19, 439–453. [Google Scholar] [CrossRef]
- Georgakopoulou, E.A.; Tsimaratou, K.; Evangelou, K.; Marcos-PJ, F.; Zoumpourlis, V. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging 2013, 5, 37–50. [Google Scholar] [CrossRef] [Green Version]
- Hernandez-Segura, A.; Nehme, J.; Demaria, M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018, 28, 436–453. [Google Scholar] [CrossRef]
- Freund, A.; Laberge, R.M.; Demaria, M.; Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 2012, 23, 2066–2075. [Google Scholar] [CrossRef]
- Adams, P.D.; Ivanov, A.; Pawlikowski, J.; Manoharan, I.; Tuyn, J.; Nelson, D.M.; Singh Rai, T.; Shah, P.P.; Hewitt, G.; Korolchuk, V.I.; et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 2013, 202, 129–143. [Google Scholar]
- 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.; et al. Senescence-associated reprogramming promotes cancer stemness. Nature 2018, 553, 96–100. [Google Scholar] [CrossRef] [Green Version]
- Mosieniak, G.; Sliwinska, M.A.; Alster, O.; Strzeszewska, A.; Sunderland, P.; Piechota, M.; Was, H.; Sikora, E. Polyploidy Formation in Doxorubicin-Treated Cancer Cells Can Favor Escape from Senescence. Neoplasia 2015, 17, 882–893. [Google Scholar] [CrossRef] [Green Version]
- Taymaz-Nikerel, H.; Karabekmez, M.E.; Eraslan, S.; Kırdar, B. Doxorubicin induces an extensive transcriptional and metabolic rewiring in yeast cells. Sci. Rep. 2018, 8, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lewinska, A.; Adamczyk-Grochala, J.; Kwasniewicz, E.; Deregowska, A.; Wnuk, M. Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity. Toxicol. Lett. 2017, 265, 117–130. [Google Scholar] [CrossRef]
- Camorani, S.; Cerchia, L.; Fedele, M.; Erba, E.; D’Incalci, M.; Crescenzi, E. Trabectedin modulates the senescence-associated secretory phenotype and promotes cell death in senescent tumor cells by targeting NF-κB. Oncotarget 2018, 9, 19929–19944. [Google Scholar] [CrossRef] [Green Version]
- Chang, B.D.; Broude, E.V.; Dokmanovic, M.; Zhu, H.; Ruth, A.; Xuan, Y.; Kandel, E.S.; Lausch, E.; Christov, K.; Roninson, I.B. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 1999, 59, 3761–3767. [Google Scholar] [PubMed]
- Bojko, A.; Czarnecka-Herok, J.; Charzynska, A.; Dabrowski, M.; Sikora, E. Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents. Cells 2019, 8, 1501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Elmore, L.W.; Rehder, C.W.; Di, X.; McChesney, P.A.; Jackson-Cook, C.K.; Gewirtz, D.A.; Holt, S.E. Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J. Biol. Chem. 2002, 277, 35509–35515. [Google Scholar] [CrossRef] [Green Version]
- Jackson, J.G.; Pereira-Smith, O.M. Primary and Compensatory Roles for RB Family Members at Cell Cycle Gene Promoters That Are Deacetylated and Downregulated in Doxorubicin-Induced Senescence of Breast Cancer Cells. Mol. Cell. Biol. 2006, 26, 2501–2510. [Google Scholar] [CrossRef] [Green Version]
- Huun, J.; Lønning, P.E.; Knappskog, S. Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines. Cell Death Discov. 2017, 3, 1–6. [Google Scholar] [CrossRef]
- Jackson, J.G.; Pant, V.; Li, Q.; Chang, L.L.; Quintás-Cardama, A.; Garza, D.; Tavana, O.; Yang, P.; Manshouri, T.; Li, Y.; et al. P53-Mediated Senescence Impairs the Apoptotic Response to Chemotherapy and Clinical Outcome in Breast Cancer. Cancer Cell 2012, 21, 793–806. [Google Scholar] [CrossRef] [Green Version]
- Inao, T.; Kotani, H.; Iida, Y.; Kartika, I.D.; Okimoto, T.; Tanino, R.; Shiba, E.; Harada, M. Different sensitivities of senescent breast cancer cells to immune cell-mediated cytotoxicity. Cancer Sci. 2019, 110, 2690–2699. [Google Scholar] [CrossRef]
- Nemade, H.; Chaudhari, U.; Acharya, A.; Hescheler, J.; Hengstler, J.G.; Papadopoulos, S.; Sachinidis, A. Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch. Toxicol. 2018, 92, 1507–1524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Te Poele, R.H.; Okorokov, A.L.; Jardine, L.; Cummings, J.; Joel, S.P. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002, 62, 1876–1883. [Google Scholar] [PubMed]
- Wu, D.; Pepowski, B.; Takahashi, S.; Kron, S.J. A cmap-enabled gene expression signature-matching approach identifies small-molecule inducers of accelerated cell senescence. BMC Genom. 2019, 20, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Wang, Y.; Liu, S.; Liu, Y.; Xu, H.; Liang, J.; Zhu, J.; Zhang, G.; Su, W.; Dong, W.; et al. Upregulation of EID3 sensitizes breast cancer cells to ionizing radiation-induced cellular senescence. Biomed. Pharmacother. 2018, 107, 606–614. [Google Scholar] [CrossRef]
- Santarosa, M.; Del Col, L.; Tonin, E.; Caragnano, A.; Viel, A.; Maestro, R. Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: Implication for tailored treatments of BRCA1 mutation carriers. Mol. Cancer Ther. 2009, 8, 844–854. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shamanna, R.A.; Lu, H.; Croteau, D.L.; Arora, A.; Agarwal, D.; Ball, G.; Aleskandarany, M.A.; Ellis, I.O.; Pommier, Y.; Madhusudan, S.; et al. Camptothecin targets WRN protein: Mechanism and relevance in clinical breast cancer. Oncotarget 2016, 7, 13269–13284. [Google Scholar] [CrossRef] [Green Version]
- Opresko, P.L.; Calvo, J.P.; von Kobbe, C. Role for the Werner syndrome protein in the promotion of tumor cell growth. Mech. Aging Dev. 2007, 128, 423–436. [Google Scholar] [CrossRef]
- Xie, L.; Zhao, T.; Cai, J.; Su, Y.; Wang, Z.; Dong, W. Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells. OncoTargets Ther. 2016, 9, 7115–7122. [Google Scholar] [CrossRef] [Green Version]
- Chan, A.; Gilfillan, C.; Templeton, N.; Paterson, I.; Northcote, P.T.; Miller, J.H. Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A. Invest. New Drugs 2017, 35, 706–717. [Google Scholar] [CrossRef]
- Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer 2003, 3, 330–338. [Google Scholar] [CrossRef]
- Milczarek, M.; Wiktorska, K.; Mielczarek, L.; Koronkiewicz, M.; Dąbrowska, A.; Lubelska, K.; Matosiuk, D.; Chilmonczyk, Z. Autophagic cell death and premature senescence: New mechanism of 5-fluorouracil and sulforaphane synergistic anticancer effect in MDA-MB-231 triple negative breast cancer cell line. Food Chem. Toxicol. 2018, 111, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Cerrito, M.G.; Pelizzoni, D.; Bonomo, S.M.; Digiacomo, N.; Scagliotti, A.; Bugarin, C.; Gaipa, G.; Grassilli, E.; Lavitrano, M.; Giovannoni, R.; et al. Metronomic combination of Vinorelbine and 5-Fluorouracil inhibit triple-negative breast cancer cells results from the proof of- concept VICTOR-0 study. Oncotarget 2018, 9, 27448–27459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kavanagh, E.L.; Lindsay, S.; Halasz, M.; Gubbins, L.C.; Weiner-Gorzel, K.; Guang, M.H.Z.; McGoldrick, A.; Collins, E.; Henry, M.; Blanco-Fernández, A.; et al. Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells. Oncogenesis 2017, 6, e388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stanton, R.A.; Gernert, K.M.; Nettles, J.H.; Aneja, R. ChemInform Abstract: Drugs that Target Dynamic Microtubules: A New Molecular Perspective. ChemInform 2011, 31, 443–481. [Google Scholar] [CrossRef]
- Meng, P.; Ghosh, R. Transcription addiction: Can we garner the Yin and Yang functions of E2F1 for cancer therapy? Cell Death Dis. 2014, 5, e1360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laine, A.; Sihto, H.; Come, C.; Rosenfeldt, M.T.; Zwolinska, A.; Niemelä, M.; Khanna, A.; Chan, E.K.; Kähäri, V.-M.; Kellokumpu-Lehtinen, P.-L.; et al. Senescence Sensitivity of Breast Cancer Cells Is Defined by Positive Feedback Loop between CIP2A and E2F1. Cancer Discov. 2013, 3, 182–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lingling, D.; Kristen, S.; Sergey, K.; Heetae, K.; Powel, H.; Brown, T.C.C. Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest. Biochem. Pharmacol. 2007, 73, 481–490. [Google Scholar]
- Lukey, M.J.; Greene, K.S.; Erickson, J.W.; Wilson, K.F.; Cerione, R.A. The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat. Commun. 2016, 7, 1–14. [Google Scholar] [CrossRef]
- Groth-Pedersen, L.; Ostenfeld, M.S.; Høyer-Hansen, M.; Nylandsted, J.; Jäättelä, M. Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res. 2007, 67, 2217–2225. [Google Scholar] [CrossRef] [Green Version]
- Gomes, L.R.; Rocha, C.R.R.; Martins, D.J.; Fiore, A.P.Z.P.; Kinker, G.S.; Bruni-Cardoso, A.; Menck, C.F.M. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. Cell Death Dis. 2019, 10, 1–15. [Google Scholar] [CrossRef]
- Hill, D.P.; Harper, A.; Malcolm, J.; McAndrews, M.S.; Mockus, S.M.; Patterson, S.E.; Reynolds, T.; Baker, E.J.; Bult, C.J.; Chesler, E.J.; et al. Cisplatin-resistant triple-negative breast cancer subtypes: Multiple mechanisms of resistance. BMC Cancer 2019, 19, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Shi, Y.; Huang, D.; Guan, X. Emerging therapeutic modalities of PARP inhibitors in breast cancer. Cancer Treat. Rev. 2018, 68, 62–68. [Google Scholar] [CrossRef] [PubMed]
- Fleury, H.; Malaquin, N.; Tu, V.; Gilbert, S.; Martinez, A.; Olivier, M.A.; Sauriol, A.; Communal, L.; Leclerc-Desaulniers, K.; Carmona, E.; et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat. Commun. 2019, 10, 1–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tuttle, R.; Miller, K.R.; Maiorano, J.N.; Termuhlen, P.M.; Gao, Y.; Berberich, S.J. Novel senescence associated gene, YPEL3, is repressed by estrogen in ER+ mammary tumor cells and required for tamoxifen-induced cellular senescence. Int. J. Cancer 2012, 130, 2291–2299. [Google Scholar] [CrossRef] [PubMed]
- Kelley, K.D.; Miller, K.R.; Todd, A.; Kelley, A.R.; Tuttle, R.; Berberich, S.J. YPEL3, a p53-regulated gene that induces cellular senescence. Cancer Res. 2010, 70, 3566–3575. [Google Scholar] [CrossRef] [Green Version]
- Lee, Y.H.; Kang, B.S.; Bae, Y.S. Premature senescence in human breast cancer and colon cancer cells by tamoxifen-mediated reactive oxygen species generation. Life Sci. 2014, 97, 116–122. [Google Scholar] [CrossRef]
- Trembley, J.H.; Wang, G.; Unger, G.; Slaton, J.; Ahmed, K. Protein kinase CK2 in health and disease: CK2: A key player in cancer biology. Cell. Mol. Life Sci. 2009, 66, 1858–1867. [Google Scholar] [CrossRef] [Green Version]
- Dolfi, S.C.; Jäger, A.V.; Medina, D.J.; Haffty, B.G.; Yang, J.M.; Hirshfield, K.M. Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs. Physiol. Behav. 2017, 176, 139–148. [Google Scholar] [CrossRef] [Green Version]
- McDermott, M.S.J.; Conlon, N.; Browne, B.C.; Szabo, A.; Synnott, N.C.; O’brien, N.A.; Duffy, M.J.; Crown, J.; O’donovan, N. HER2-targeted tyrosine kinase inhibitors cause therapy-induced-senescence in breast cancer cells. Cancers 2019, 11, 197. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.; Xu, B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct. Target. Ther. 2019, 4, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Hattangadi, D.K.; DeMasters, G.A.; Walker, T.D.; Jones, K.R.; Di, X.; Newsham, I.F.; Gewirtz, D.A. Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell. Biochem. Pharmacol. 2004, 68, 1699–1708. [Google Scholar] [CrossRef]
- Korobeynikov, V.; Borakove, M.; Feng, Y.; Wuest, W.M.; Koval, A.B.; Nikonova, A.S.; Serebriiskii, I.; Chernoff, J.; Borges, V.F.; Golemis, E.A.; et al. Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer. Breast Cancer Res. Treat. 2019, 177, 369–382. [Google Scholar] [CrossRef] [Green Version]
- Tentler, J.J.; Ionkina, A.A.; Tan, A.C.; Newton, T.P.; Pitts, T.M.; Glogowska, M.J.; Kabos, P.; Sartorius, C.A.; Sullivan, K.D.; Espinosa, J.M.; et al. P53 family members regulate phenotypic response to Aurora kinase a inhibition in Triple-negative breast cancer. Mol. Cancer Ther. 2015, 14, 1117–1129. [Google Scholar] [CrossRef] [Green Version]
- Yin, T.; Zhao, Z.; Guo, J.; Wang, T.; Yang, J.B.; Wang, C.; Long, J.; Ma, S.; Huang, Q.; Zhang, K.; et al. Aurora A inhibition eliminates myeloid cell- mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in breast cancer. Cancer Res. 2019, 79, 3431–3444. [Google Scholar] [CrossRef] [Green Version]
- Wang, L.; Leite de Oliveira, R.; Wang, C.; Fernandes Neto, J.M.; Mainardi, S.; Evers, B.; Lieftink, C.; Morris, B.; Jochems, F.; Willemsen, L.; et al. High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer. Cell Rep. 2017, 21, 773–783. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Li, P.; Pan, H.; Liu, L.; Ji, M.; Sheng, N.; Wang, C.; Cai, L.; Ma, Y. Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy. Biomaterials 2016, 83, 219–232. [Google Scholar] [CrossRef] [PubMed]
- He, J.; Du, L.; Bao, M.; Zhang, B.; Qian, H.; Zhou, Q.; Cao, Z. Oroxin A inhibits breast cancer cell growth by inducing robust endoplasmic reticulum stress and senescence. Anticancer Drugs 2016, 27, 204–215. [Google Scholar] [CrossRef] [PubMed]
- Chakraborty, S.; Rasool, R.; Kumar, S.; Nayak, D.; Rah, B.; Katoch, A.; Amin, H.; Ali, A.; Goswami, A. Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1. Age 2016, 38, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.B.; Gao, J.L.; Zhong, Z.F.; Hoi, P.M.; Lee, S.M.Y.; Wang, Y.T. Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways. Pharmacol. Rep. 2013, 65, 700–709. [Google Scholar] [CrossRef]
- Manuscript, A. NIH Public Access. J. Cell. Biochem. 2015, 115, 2103–2115. [Google Scholar]
- Lee, Y.H.; Yuk, H.J.; Park, K.H.; Bae, Y.S. Coumestrol induces senescence through protein kinase CKII inhibition-mediated reactive oxygen species production in human breast cancer and colon cancer cells. Food Chem. 2013, 141, 381–388. [Google Scholar] [CrossRef]
- Mileo, A.M.; Di Venere, D.; Abbruzzese, C.; Miccadei, S. Long term exposure to polyphenols of artichoke (cynara scolymus L.) Exerts induction of senescence driven growth arrest in the MDA-MB231 human breast cancer cell line. Oxid. Med. Cell. Longev. 2015, 11. [Google Scholar] [CrossRef] [Green Version]
- Lewinska, A.; Adamczyk-Grochala, J.; Deregowska, A.; Wnuk, M. Sulforaphane-induced cell cycle arrest and senescence are accompanied by DNA hypomethylation and changes in microRNA profile in breast cancer cells. Theranostics 2017, 7, 3461–3477. [Google Scholar] [CrossRef] [PubMed]
- Ji, S.; Zheng, Z.; Liu, S.; Ren, G.; Gao, J.; Zhang, Y.; Li, G. Resveratrol Promotes Oxidative Stress to Drive DLC1 Mediated Cellular Senescence in Cancer Cells; Elsevier: Amsterdam, The Netherlands, 2018; Volume 370. [Google Scholar]
- Kim, K.Y.; Park, K.; Kim, S.H.; Yu, S.N.; Lee, D.; Kim, Y.W.; Noh, K.T.; Ma, J.Y.; Seo, Y.K.; Ahn, S.C. Salinomycin induces reactive oxygen species and apoptosis in aggressive breast cancer cells as mediated with regulation of autophagy. Anticancer Res. 2017, 37, 1747–1758. [Google Scholar] [PubMed]
- Pierpaoli, E.; Viola, V.; Barucca, A.; Orlando, F.; Galli, F.; Provinciali, M. Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice. Carcinogenesis 2013, 34, 1352–1360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Afanas’ev, I. New nucleophilic mechanisms of ROS-dependent epigenetic modifications: Comparison of aging and cancer. Aging Dis. 2014, 5, 52–62. [Google Scholar] [CrossRef] [PubMed]
- Cagnol, S.; Chambard, J. MINIREVIEW ERK and cell death: Mechanisms of ERK-induced cell death—Apoptosis, autophagy and senescence. FEBS J. 2010, 2, 2–21. [Google Scholar] [CrossRef]
- El Hasasna, H.; Athamneh, K.; Al Samri, H.; Karuvantevida, N.; Al Dhaheri, Y.; Hisaindee, S.; Ramadan, G.; Al Tamimi, N.; AbuQamar, S.; Eid, A.; et al. Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation. Sci. Rep. 2015, 5, 1–18. [Google Scholar] [CrossRef] [Green Version]
- Yu, C.C.; Ko, F.Y.; Yu, C.S.; Lin, C.C.; Huang, Y.P.; Yang, J.S.; Lin, J.P.; Chung, J.G. Norcantharidin triggers cell death and DNA damage through S-phase arrest and ROS-modulated apoptotic pathways in TSGH 8301 human urinary bladder carcinoma cells. Int. J. Oncol. 2012, 41, 1050–1060. [Google Scholar] [CrossRef]
- He, Q.; Xue, S.; Tan, Y.; Zhang, L.; Shao, Q.; Xing, L.; Li, Y.; Xiang, T.; Luo, X.; Ren, G. Dual inhibition of Akt and ERK signaling induces cell senescence in triple-negative breast cancer. Cancer Lett. 2019, 448, 94–104. [Google Scholar] [CrossRef]
- Al Dhaheri, Y.; Attoub, S.; Arafat, K.; Abuqamar, S.; Eid, A.; Al Faresi, N.; Iratni, R. Salinomycin induces apoptosis and senescence in breast cancer: Upregulation of p21, downregulation of survivin and histone H3 and H4 hyperacetylation. Biochim. Biophys. Acta Gen. Subj. 2013, 1830, 3121–3135. [Google Scholar] [CrossRef] [PubMed]
- Mosieniak, G.; Sliwinska, M.A.; Przybylska, D.; Grabowska, W.; Sunderland, P.; Bielak-Zmijewska, A.; Sikora, E. Curcumin-treated cancer cells show mitotic disturbances leading to growth arrest and induction of senescence phenotype. Int. J. Biochem. Cell Biol. 2016, 74, 33–43. [Google Scholar] [CrossRef] [PubMed]
- So, A.Y.; Jung, J.W.; Lee, S.; Kim, H.S.; Kang, K.S. DNA methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS ONE 2011, 6, e19503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, C.; Xu, C.X.; Bu, Y.; Bottum, K.M.; Tischkau, S.A. Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling. Carcinogenesis 2014, 35, 703–713. [Google Scholar] [CrossRef] [Green Version]
- Yuen, H.F.; Abramczykd, O.; Montgomery, G.; Chan, K.K.; Huang, Y.H.; Sasazuki, T.; Shirasawa, S.; Gopesh, S.; Chan, K.W.; Fennell, D.; et al. Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells. Biosci. Rep. 2012, 32, 413–422. [Google Scholar] [CrossRef]
- Srinivasan, M.; Bharali, D.J.; Sudha, T.; Khedr, M.; Guest, I.; Sell, S.; Glinsky, G.V.; Mousa, S.A. Downregulation of Bmi1 in breast cancer stem cells suppresses tumor growth and proliferation. Oncotarget 2017, 8, 38731–38742. [Google Scholar] [CrossRef] [Green Version]
- Guillon, J.; Petit, C.; Moreau, M.; Toutain, B.; Henry, C.; Roché, H.; Bonichon-Lamichhane, N.; Salmon, J.P.; Lemonnier, J.; Campone, M.; et al. Regulation of senescence escape by TSP1 and CD47 following chemotherapy treatment. Cell Death Dis. 2019, 10, 199. [Google Scholar] [CrossRef]
- Shahul, S.; Tung, A.; Minhaj, M.; Nizamuddin, J.; Wenger, J.; Mahmood, E.; Mueller, A.; Shaefi, S.; Scavone, B.; Kociol, R.D.; et al. 2017 Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein BMI1 in Breast Cancer Cells Joseph. Physiol. Behav. 2017, 176, 139–148. [Google Scholar]
- Liu, J.; Duan, Z.; Guo, W.; Zeng, L.; Wu, Y.; Chen, Y.; Tai, F.; Wang, Y.; Lin, Y.; Zhang, Q.; et al. Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nat. Commun. 2018, 9, 1–17. [Google Scholar] [CrossRef]
- Provinciali, M.; Papalini, F.; Orlando, F.; Pierpaoli, S.; Donnini, A.; Morazzoni, P.; Riva, A.; Smorlesi, A. Effect of the silybin-phosphatidylcholine complex (IdB 1016) on the development of mammary tumors in HER-2/neu transgenic mice. Cancer Res. 2007, 67, 2022–2029. [Google Scholar] [CrossRef] [Green Version]
- Pierpaoli, E.; Arcamone, A.G.; Buzzetti, F.; Lombardi, P.; Salvatore, C.; Provinciali, M. Antitumor effect of novel berberine derivatives in breast cancer cells. BioFactors 2013, 39, 672–679. [Google Scholar] [CrossRef]
- Saleh, T.; Tyutyunyk-Massey, L.; Murray, G.F.; Alotaibi, M.R.; Kawale, A.S.; Elsayed, Z.; Henderson, S.C.; Yakovlev, V.; Elmore, L.W.; Toor, A.; et al. Tumor cell escape from therapy-induced senescence. Biochem. Pharmacol. 2019, 162, 202–212. [Google Scholar] [CrossRef] [PubMed]
- Hou, J.G.; Jeon, B.M.; Yun, Y.J.; Cui, C.H.; Kim, S.C. Ginsenoside Rh2 ameliorates doxorubicin-induced senescence bystander effect in breast carcinoma cell MDA-MB-231 and normal epithelial cell MCF-10A. Int. J. Mol. Sci. 2019, 20, 1244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, L.M.; Zhang, J.; Zhang, Y.; Fei, C.; Wang, L.; Yi, Z.W.; Zhang, Z.Q. Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression. Biomed. Pharmacother. 2019, 113, 108756. [Google Scholar] [CrossRef]
- Kandhaya-Pillai, R.; Miro-Mur, F.; Alijotas-Reig, J.; Tchkonia, T.; Kirkland, J.L.; Schwartz, S. TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion. Aging 2017, 9, 2411–2435. [Google Scholar] [CrossRef] [Green Version]
- Liu, M.; Guo, S.; Stiles, J.K. The emerging role of CXCL10 in cancer. Oncol. Lett. 2011, 2, 583–589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saleh, T.; Tyutynuk-Massey, L.; Cudjoe, E.K.; Idowu, M.O.; Landry, J.W.; Gewirtz, D.A. Non-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy. Front. Oncol. 2018, 8, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hasan, M.R.; Ho, S.H.Y.; Owen, D.A.; Tai, I.T. Inhibition of VEGF induces cellular senescence in colorectal cancer cells. Int. J. Cancer 2011, 129, 2115–2123. [Google Scholar] [CrossRef]
- Thorn, M.; Guha, P.; Cunetta, M.; Espat, N.J.; Miller, G.; Junghans, R.P.; Katz, S.C. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gen. Ther. 2016, 23, 188–198. [Google Scholar] [CrossRef]
- Radisky, E.S.; Radisky, D.C. Matrix metalloproteinases as breast cancer drivers and therapeutic targets. Front. Biosci. Landmark 2015, 20, 1144–1163. [Google Scholar] [CrossRef]
- Demaria, M.; O’Leary, M.N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A.M.; et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017, 7, 165–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perrott, K.M.; Wiley, C.D.; Desprez, P.Y.; Campisi, J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. GeroScience 2017, 39, 161–173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, Y.; Tchkonia, T.; Pirtskhalava, T.; Gower, A.C.; Ding, H.; Giorgadze, N.; Palmer, A.K.; Ikeno, Y.; Hubbard, G.B.; Hara, S.P.O.; et al. The Achilles’ heel of 1350 senescent cells: From transcriptome to senolytic drugs. Aging Cell 2015, 14, 644–658. [Google Scholar] [CrossRef]
- Fuhrmann-stroissnigg, H.; Ling, Y.Y.; Zhao, J.; Mcgowan, S.J.; Zhu, Y.; Brooks, R.W.; Grassi, D.; Gregg, S.Q.; Stripay, J.L.; Dorronsoro, A.; et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 2017, 8, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Cesar, P.; Lazareno, O.; Id, O. Differential Effects of Alliin and Allicin on Apoptosis and Senescence in Luminal A and Triple-negative Breast Cancer: Caspase, ΔΨm, and Pro- apoptotic Gene Involvement. Fundam. Clin. Pharmacol. 2020. [Google Scholar] [CrossRef]
- Hubackova, S.; Davidova, E.; Rohlenova, K.; Stursa, J.; Werner, L.; Andera, L.; Dong, L.F.; Terp, M.G.; Hodny, Z.; Ditzel, H.J.; et al. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ. 2019, 26, 276–290. [Google Scholar] [CrossRef] [Green Version]
- Triana-Martínez, F.; Picallos-Rabina, P.; Da Silva-Álvarez, S.; Pietrocola, F.; Llanos, S.; Rodilla, V.; Soprano, E.; Pedrosa, P.; Ferreirós, A.; Barradas, M.; et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 2019, 10, 1–12. [Google Scholar] [CrossRef]
Subtype | Immunochemistry Markers | Systemic Therapy | Overview |
---|---|---|---|
luminal A | ER+ and/or PR+, HER2− and low Ki67 | hormonal therapy |
|
luminal B | HER negative: ER+ and/or PR+ or high Ki-67 | hormonal therapy + chemotherapy |
|
HER positive: ER+ and any PR−, any Ki-67 | hormonal therapy +anty-HER therapy + chemotherapy | ||
HER2-enriched | ER−, PR−, HER2+ | anty-HER therapy (humanized monoclonal antibodies and small kinase inhibitors ) + chemotherapy |
|
basal-like | ER−, PR−, HER2−, CK5/6+, and/or EGFR+ | chemotherapy |
|
Change | Markers | Methods |
---|---|---|
increased lysosomal content | ↑senescence-associated beta-galactosidase (SA-β-gal) ↑lipofuscin | x-gal biochemical assay cytometric quantification of C12FDG fluorogenic β-galactosidase substrate Sudan Black B staining |
permanent cell cycle arrest | ↑cell cycle inhibitors: p21, p16,p19 | mRNA level and protein level determination methods |
DNA damage | ↑γH2AX (a phosphorylated form of the histone variant H2AX) and 53BP1 (p53 binding protein 1) ↑ phosphorylated p53 | immunostaining/immunoblotting |
loss of the proliferation activity | ↓Ki67 protein or 5-bromodeoxyuridine incorporation (expect the case of polyploidization during senescence [8]) | immunostaining |
loss of the nuclear envelope integrity | ↓LaminB1 [17] ↑cytoplasmic chromatin fragments (CCFs) [18] | mRNA level and protein level determination methods DAPI staining |
senescence-associated heterochromatin foci (SAHF) | ↑ the histone H2A variant macroH2A, ↑heterochromatin protein 1 (HP1) proteins ↑ lysine 9 di-or tri-methylated histone H3 (H3K9Me2/3) | immunofluorescence staining |
SASP | ↑interleukins e.g. IL-6, IL-1a, IL-1b ↑chemokines e.g. IL-8, ↑cytokines such as colony-stimulating factors (CSFs) e.g. GM-CSF, ↑growth factor expression e.g., vascular epithelial growth factor (VEGF) ↑proteases such as metalloproteinases e.g.,MMP-1 and MMP-3, collagenase-1 (MMP-1) [13] | ELISA in culture medium |
Drug | Cell line, (Concentrations) | Senescence Markers and Mechanism |
---|---|---|
doxorubicin | MCF-7, MDA-MB-231 (100 nM) | positive SA-β-gal staining, characteristic morphology, increased percentage of granular cells, γH2AX and 53BP1 foci, increased level of p-ATM and p21expression SASP: IL-8, VEGFR [25] |
MCF-7 (1 μM) | positive SA-β-gal staining, p53/p21 pathway activation, telomere-related cytogenetic abnormalities induction [26] | |
MCF-7, ZR-75 (1 μM) | p53/p21 pathway activation, G1 and G2 cell cycle block, increased p130 and decreased RB and p107 protein expression [27] | |
MCF-7, T47D, HTB-122, CRL2324 (0.5 and 1 μM) | positive SA-β-gal staining, concomitant inactivation of P53 and RB genes lead to inhibition senescence [28] | |
MCF-7, ZR-75.1 cells and a different status of p53 MMTV-Wnt1 mice | positive SA-β-gal staining, p53, and p21 pathway dependence ceased incorporating BrdU, characteristic morphology, phosphorylation of STAT3, SASP: IFNg, IL-6, CXCL2, TNFa, CXCR2, CXCL1 [29] | |
MDA-MB-231 (250 nM), BT-549 (100 nM), MCF-7 (200 nM) | positive SA-β-gal staining, γH2AX expression, elevated p21 or p16 expression, SASP: IL-6, IL-8 (only MDA-MB-231, BT-549) [30] | |
etoposide | MCF-7 (2 μM) | positive SA-β-gal staining, morphology, G1 cell cycle phase block [32] |
MCF-7 p21 (with ectopic expression of p21) (10 μM) | raised formation 53BP1 foci (24h), increased activity of SA-β-gal (5 days) [33] | |
BRCA1-deficient (HBL100-, MCF7-, and T47D-derived clones with a silenced BRCA1) and BRCA1-proficient cells (HBL100, MCF7, and T47D) (2.5 and 5 μM) | the activity of SA-β-gal independent on BRCA1 [35] | |
SN-38 | MCF-7 (100 ng/mL) | large, flatted, resistant to apoptosis and SA-β-gal-positive cells [32] |
camptothecin | MCF-7, T47D, ZR-75-1 (10 μM) | positive SA-β-gal staining, the decrease in WRN expression enhanced senescence intensity [36] |
irinotecan | MDA-MB-231, MC-7 (5 μM) | positive SA-β-gal staining, elevation level of following markers: p-ATM, percent of granularity in cells, increased in 53BP1 and γH2AX and secretion SASP: VEGF and IL-8 [25] |
methotrexate | MCF-7 (10 μM) | positive SA-β-gal staining, p53 and p21 [61] |
MCF-7 (2.5 μM) MDA-Mb-231 (30 μM) | 53BP1 and γH2AX foci observation, cells stained via SA-β-gal, many flatted and large cells, granularity increased, expression of p53 (phosphorylated and not unphosphorylated forms), p21, γH2AX grew, SASP: VEGF and IL-8 [25] | |
paclitaxel | MCF-7 (3.3 nM) | positive SA-β-gal staining, elevation of p53 expression levels, decrease in pRB level [39] |
MCF-7 (56 nM) MDA-MB-231 (5μM) | positive SA-β-gal staining, flatted and large cells elevation of p21expresssion, γH2AX, and 53BP1 foci observation elevated expression of the following proteins: p21,p53, γH2AX, increased % of granularity in the cells, SASP: VEGF [25] | |
MDA-MB-231, Cal51 (75 nM) | positive SA-β-gal staining, G2/M cell cycle block, increased of p21 and p16 expression, intensive production of EV contains drug [43] | |
vinorelbine | MCF-7 (20 nM and 30 nM) | positive SA-β-gal staining, flattened cellular morphology, increase in p21 expression, inhibition of E2F1 and CIP2A protein expression [46] |
vinblastine | MCF-7 (0.3 μM) | positive SA-β-gal staining, decrease in c-Jun expression, drop of AP-1 activation [47] |
vincristine | MCF-7 (0.3 μM) | large, flatted and multinucleated cells, G2/M cell cycle block, an increase in the size of individual lysosomes and the total volume of the lysosomal compartment [49] |
cisplatin | MDA-MB-231, MCF-7 (60 μM) | positive SA-β-gal staining, the rise in γ-H2AX level and the mRNA expression level of p21, activation ATR-Chk1 pathway via elevated REV3L expression [50] |
olaparib | MDA-MD-231 (2.5 µM) | positive SA-β-gal staining, G2/M phase cell cycle block, decrease in DNA synthesis, drop in expression of the following genes: p21, CHK2, IL-6, IL-8, and BCL-XL [53] |
tamoxifen | MCF-7 (0.5 μM) | positive SA-β-gal staining, YPEL3 expression dependent senescence [54] |
MCF-7 (5 and 10μM) | positive SA-β-gal staining, decrease CK2 activity, ROS production, activation p53–p21Cip1/WAF dependent pathway [56] | |
fulvestrant | MCF7, T47D (5, 10, 50 µM) | positive SA-β-gal staining, reduction in both ERα and MDM2 [58] |
lapatinib neratinib | SKBR3 (250 nM), HCC1419 (250 nM), EFM-192A (250 nM), MDA-MB-361 (500 nM), MDA-MB-453 (1 µM) MCF7 (1 µM) | positive SA-β-gal staining, increase in p15, p27 expression [59] |
Natural Compounds | Cell Lines or Other Models, (Concentration) | Detection and Effects |
---|---|---|
I. Flavonoids | ||
diosmin | MDA-MB-231, MCF-7, SK-BR-3, (5 and 10 µM) | positive SA-β-gal staining, an increase in the levels of p53, p27, p21, G2/M phase of cell cycle arrest, ROS production, cytostatic autophagy accompanied SISP, only in MDA-MB-231 and SK-BR-3 cells: ERK1/2 activation only in MCF-7 cells epigenetic changes (hypomethylating agent), DSBs, SSBs (single-strand breaks) [22] |
silybin (silymarin flavonoids) complex with phosphatidylcholine | SK-BR-3 (63.2, and 126.5 mg/mL), mouse models for HER2-overexpressed breast cancer (414 µmol/L/kg silybin) | positive SA-β-gal staining, cells with enlarged and flattened morphology, down-regulation of HER-2/neu expression, an increase in expression of p53 mRNA, additional in mammary tumors: the boost of the number of neutrophils, CD4, and CD8 lymphocytes, reduction of the average mean tumor number, decreasing the percentage of mice with metastasis [91] |
oroxin A | MDA-MB-231 (5 ÷ 20 µM) | positive SA-β-gal staining, SAHF, G2/M phase of cell cycle arrest, increased expression of p21 (both protein and mRNA), reorganization of microtubules and actin cytoskeleton, ROS production, endoplasmic reticulum (ER) stress-mediated senescence expression of ER stress markers (ATF4 and GRP78), elevated phosphorylation of p38 [67] |
betanaphthoflavone | MCF-7 (10 µM) | positive SA-β-gal staining, G0/G1 phase of cell cycle arrest, downregulation of cyclin D1/D3, CDK4, increased in the expression of p21, activation MAPK-ERK signaling, AhR-dependent inhibition of the PI3K/Akt pathway [85] |
cristacarpin | MDA-MB-231 (1, 5, 10 µM) 4T1 cells implanted into Balb/c mice (950 mg/kg/body weight) | positive SA-β-gal staining, cells with enlarged and flattened morphology, SAHF, G0/G1 phase of cell cycle arrest, p21upregulation, ROS production, decrease in the expression of Cdk-2, cyclinD1, activation MAP kinase pathway, ER stress (amplification of expression markers viz. GRP-78, GRP-94, and PERK) positive SA-β-gal staining, inhibition growth and development of tumor [68] |
coumestrol | MCF-7 (10 ÷ 50 µM) | positive SA-β-gal staining, activation of the p53-p21 pathway, ROS production, inhibition of CKII [71] |
II. Non-flavonoids | ||
curcumin | MCF-7 (10 and 15 µM) | positive SA-β-gal staining, mitotic arrest, the lack of BrdU incorporation, 53BP1 and γH2AX foci, increase in the level of γH2AX, p53 and p21 proteins, the structure of mitotic spindle disturbances [83] |
bisdemethoxycurcumin | MCF-7 (20 µM) | ROS production, activation of p53/p21 and p16/Rb pathways, a reduction of mG2/M phase of cell cycle arrest [69] |
peloruside A | MCF-7 (9.6 nM) | positive SA-β-gal staining, G0/G1 phase of cell cycle arrest, elevated expression of p53 [39] |
polyphenols extracted from artichoke | MDA-MB231 (30 µM) | positive SA-β-gal staining, upregulation of p16, p21, ROS production, epigenetic alterations (modulating DNA hypomethylation and increase of lysine acetylation) [72] |
norcantharidin | MDA-MB-231 (21.83 µM) MDA-MB-231 implanted into mice model with injected, (28 mg/kg) | positive SA-β-gal staining, decrease in phosphorylation of Akt and ERK1/2, rise in p21 p16 level and γ-H2AX expression level, G2/M phase of cell cycle arrest, SASP: IL-6, IL-8 and IL-1β, MMP-1, MMP-3 Additionally in the mouse model: decrease in tumor volume [81] |
timosaponin A-III | MDA-MB-231 and MCF7 (2 and 4 µM) | positive SA-β-gal staining, rise in expression of miR-141 and miR-200c leading to inhibited expression of BMI1, c-Myc downregulation, histone posttranslational modification activity of PRC1 [89] |
berberine derivates | SK-BR-3 (50 µM) | a rise in mRNA expression of p53, p21, p16, and PAI-1, a downregulation of HER-2/neu expression [92] |
resveratrol | MCF-7, MDA-MB-231 (20 µM) | positive SA-β-gal staining, rise in expression of p38MAPK, p27, p21, downregulation of Rb and p-Rb protein, ROS production, a reduction in the mitochondrial membrane potential, down-regulation of mitochondrial MT-ND1, MT-ND6, and ATPase8 mRNA level, decrease in PGC-1α protein level, downregulation of DNMT1, increase in DLC1 level, SIRT1, NF-κB level, SASP: IL-6, decrease in FoxO3a level [74] |
annatto-T3 | TUBO, SKBR3 (50 μM) FVB/N mice (100 mg/kg) | positive SA-β-gal staining, ROS production, decrease in the mitochondrial membrane potential, upregulation of p53, p21, and p27 mRNA, reduction in HER-2/neu mRNA expression, in mouse model—decrease in following parameters: tumor development, number and volume of the tumor, size of lung tumor metastasis [76] |
sulforaphane | MCF-7, MDA-MB-231, SK-BR-3 (5 ÷ 10 µM) | positive SA-β-gal staining, elevation in p21 and p27 levels, ROS production, DSBs, ATM phosphorylation increase, 53BP1 foci formation, epigenetic modification: DNA hypomethylation, decrease in levels of DNMT1 and DNMT3B, microRNA profile changes, cytostatic autophagy accompanied [73] |
salinomycin | MDA-MB-231 (10, 25 µM) | positive SA-β-gal staining, G2/M phase of cell cycle arrest, γH2AX foci observation, upregulation p21, histone H3 and H4 hyperacetylation [82] |
Rhus coriaria extract | MDA-MB-231 (100–600 µ/mL) | positive SA-β-gal staining, G1 phase of cell cycle arrest upregulation of p21, downregulation of cyclin D1, p27, PCNA, c-Myc, phospho-RB, no proliferative recovery, cytostatic autophagy accompanied [79] |
SASP Element | Examples | Effect |
---|---|---|
cytokines | IL-6 [23,29,30,94] IL-8 17 [25,30,88,94] IL-1α/β [88,94], | proinflammatory cytokines, maintenance of senescence, promotion of tumorigenesis and chemotherapy resistance |
IL-18 [88] | proinflammatory cytokine, induction fibroblast senescence [95] | |
TNF-α[23] IFNg [29] | proinflammatory cytokines, inductors of senescence [96] | |
IGFBPs, uPA, FGF-6 [94] | invasiveness and metastatic activity of cancer cells | |
chemokines | CXCL2, CXCR2, CXCL10 [29] CXCL11, CXCL10 [88] CXCL10 [23] | chemoattractant of monocyte and T-cell, therefore it is known as a tumor-suppressive factor [97] |
growth factors | VEGFR [25] | induction of vascular permeability during inflammation or inhibit senescence [98,99] |
GM-CSF [94] | inhibitors of antitumor immunity promote tumor progression and metastasis [100] | |
TGFβ [88] | promoting tumor progression, including evasion of immune surveillance, autocrine mitogen and cytokine production, epithelial-mesenchymal transition [88] | |
matrix enzymes | MMP1 [88] MMPs [94] | remodeling microenvironment to promote cancer initiation and development [101] |
matricellular protein | THBS1 [88] | maintenance of senescence [88] |
© 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Milczarek, M. The Premature Senescence in Breast Cancer Treatment Strategy. Cancers 2020, 12, 1815. https://doi.org/10.3390/cancers12071815
Milczarek M. The Premature Senescence in Breast Cancer Treatment Strategy. Cancers. 2020; 12(7):1815. https://doi.org/10.3390/cancers12071815
Chicago/Turabian StyleMilczarek, Małgorzata. 2020. "The Premature Senescence in Breast Cancer Treatment Strategy" Cancers 12, no. 7: 1815. https://doi.org/10.3390/cancers12071815