Author(s):
Dhania Novitasari, Riris Istighfari Jenie, Febri Wulandari, Rohmad Yudi Utomo, Dyaningtyas Dewi Pamungkas Putri, Jun-ya Kato, Edy Meiyanto
Email(s):
edy_meiyanto@ugm.ac.id
DOI:
10.52711/0974-360X.2021.00760 
Address:
Dhania Novitasari1, Riris Istighfari Jenie1,2, Febri Wulandari1, Rohmad Yudi Utomo1,3, Dyaningtyas Dewi Pamungkas Putri1,4, Jun-ya Kato5, Edy Meiyanto1,2*
1Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada (UGM), Sekip Utara, Yogyakarta 55281, Indonesia.
2Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy UGM, Sekip Utara, Yogyakarta 55281, Indonesia.
3Medicinal Chemistry Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, UGM, Sekip Utara, Yogyakarta 55281, Indonesia.
4Pharmacology and Toxicology Laboratory, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, 55281, Indonesia.
5Laboratory of Tumor Cell Biology, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
*Corresponding Author
Published In:
Volume - 14,
Issue - 8,
Year - 2021
ABSTRACT:
Triple-negative breast cancer (TNBC) remains as the deadliest cancer type due to the lack of treatment options. Hence, several attempts have been made to develop new anticancer for TNBC therapy. This study intended to challenge curcumin analog (CCA)-1.1, which is derived from pentagamavunone-1 structure, against the 4T1 cell line and TNBC cell model, covering the cytotoxic activity in correlation with cell cycle progression, apoptosis induction, reactive oxygen species (ROS) generation, and senescence evidence. The cell viability, cell cycle profile, apoptosis induction, intracellular ROS level, and senescence induction were determined in vitro using trypan blue exclusion, propidium iodide (PI) staining, Annexin-PI staining, dichlorofluorescein diacetate staining, and senescence-associated-ß-gal method. CCA-1.1 showed cytotoxic activity on 4T1 cells, giving half maximal inhibitory concentration value of 3?M, but was less toxic on non-cancerous 3T3-L1 cells. CCA-1.1 induced rapid cell death and inhibited cell cycle progression at the mitotic phase. Instead, of causing apoptosis, CCA-1.1 induced mitotic catastrophe. Furthermore, CCA-1.1 itself increased the intracellular ROS level and induced senescence, possibly through catastrophic cell death. Altogether, our preliminary study strengthens the potency of CCA-1.1 for its anticancer activities against TNBC cells and prospective to be pharmaceutically developed as a novel candidate for cancer therapy.
Cite this article:
Dhania Novitasari, Riris Istighfari Jenie, Febri Wulandari, Rohmad Yudi Utomo, Dyaningtyas Dewi Pamungkas Putri, Jun-ya Kato, Edy Meiyanto. Curcumin-like structure (CCA-1.1) induces permanent mitotic arrest (Senescence) on Triple-negative breast cancer (TNBC) cells, 4T1. Research Journal of Pharmacy and Technology. 2021; 14(8):4375-2. doi: 10.52711/0974-360X.2021.00760
Cite(Electronic):
Dhania Novitasari, Riris Istighfari Jenie, Febri Wulandari, Rohmad Yudi Utomo, Dyaningtyas Dewi Pamungkas Putri, Jun-ya Kato, Edy Meiyanto. Curcumin-like structure (CCA-1.1) induces permanent mitotic arrest (Senescence) on Triple-negative breast cancer (TNBC) cells, 4T1. Research Journal of Pharmacy and Technology. 2021; 14(8):4375-2. doi: 10.52711/0974-360X.2021.00760 Available on: https://rjptonline.org/AbstractView.aspx?PID=2021-14-8-66
REFERENCES:
1. De Santis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women: Breast Cancer Statistics, 2015. CA: A Cancer Journal for Clinicians. 2016; 66(1): 31-42. doi:10.3322/caac.21320
2. Kohler BA, Sherman RL, Howlader N, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. J Natl Cancer Inst. 2015; 107(6). doi:10.1093/jnci/djv048
3. Plasilova ML, Hayse B, Killelea BK, Horowitz NR, Chagpar AB, Lannin DR. Features of triple-negative breast cancer. Medicine (Baltimore). 2016;95(35). doi:10.1097/MD.0000000000004614
4. Hariramani N, Jayanthi S. A Systematic Review of Intrinsic Factors and its Influence in Breast Cancer. Research Journal of Pharmacy and Technology. 2018;11(8): 3543-3546. doi:10.5958/0974-360X.2018.00654.6
5. Asaad RA, Abdullah SS. Breast Cancer Subtypes (BCSs) Classification according to Hormone Receptor Status: Identification of patients at High Risk in Jableh- Syria. Research Journal of Pharmacy and Technology. 2018; 11(8): 3703-3710. doi:10.5958/0974-360X.2018.00680.7
6. Al-Shalah MAN, Al-Mosawi HM, Alaawad AS. Comparative Study between Paired Primary and Relapsed Breast Cancer Patients based on Clinicopathological Features and Molecular Subtypes of Breast Cancer in Babylon Province. Research Journal of Pharmacy and Technology. 2018;11(6):2365-2371. doi:10.5958/0974-360X.2018.00439.0
7. Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res. 2018;8(5):1483-1507. doi:10.1007/s13346-018-0551-3
8. Garrett JT, Arteaga CL. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors. Cancer Biology & Therapy. 2011; 11(9): 793-800. doi:10.4161/cbt.11.9.15045
9. Jernström S, Hongisto V, Leivonen S-K, et al. Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. Breast Cancer (Dove Med Press). 2017; 9: 185-198. doi:10.2147/BCTT.S115600
10. Thalkari AB, Karwa PN, Zambare KK, Tour NS, Chopane PS. Paclitaxel Against Cancer: A new trademarked drug. Rese Jour of Pharmac and Phytoch. 2019; 11(3): 123. doi:10.5958/0975-4385.2019.00021.9
11. Yao Y, Chu Y, Xu B, Hu Q, Song Q. Radiotherapy after surgery has significant survival benefits for patients with triple-negative breast cancer. Cancer Med. 2019;8(2):554-563. doi:10.1002/cam4.1954
12. Swapnil K, Vijay S, Chandrakant M. Targeted Drug Delivery: A Backbone for Cancer Therapy. Asian Journal of Pharmaceutical Research. 2013; 3(1): 40-46.
13. Sudhakar GK, Pai V, Pai A. An overview on current Strategies in Breast Cancer Therapy. Research Journal of Pharmacology and Pharmacodynamics. 2014; 5(6): 353-355.
14. Saha D, Maity T, Jana M, Mandal S. Cancer Treatment Strategy-An Overview. Asian Journal of Pharmacy and Technology. 2011; 1(2): 28-33.
15. Patidar A, S.C. Shivhare, Ateneriya U, Choudhary S. A Comprehensive Review on Breast Cancer. Asian Journal of Nursing Education and Research. 2012; 2(1): 28-32.
16. Dange VN, Shid SJ, Magdum CS, Mohite SK. A Review on Breast cancer: An Overview. Asian Journal of Pharmaceutical Research. 2017; 7(1): 49-51. doi:10.5958/2231-5691.2017.00008.9
17. Yadav AR, Mohite SK. Cancer- A Silent Killer: An Overview. Asian Journal of Pharmaceutical Research. 2020;10(3):213-216. doi:10.5958/2231-5691.2020.00036.2
18. Damaskos C, Garmpi A, Nikolettos K, et al. Triple-Negative Breast Cancer: The Progress of Targeted Therapies and Future Tendencies. Anticancer Res. 2019;39(10):5285-5296. doi:10.21873/anticanres.13722
19. Eldhose E, Gowramma B, Mohammed M, Kalirajan R, Kaviarasan L. Translational Chemotherapy for triple negative Breast Cancer - A Review on significance of poly (ADP-ribose) polymerase 1 (PARP 1) inhibitors. Research Journal of Pharmacy and Technology. 2019;12(6):3098-3104. doi: 10.5958/0974-360X.2019.00524.9
20. McCann KE, Hurvitz SA, McAndrew N. Advances in Targeted Therapies for Triple-Negative Breast Cancer. Drugs. 2019;79(11):1217-1230. doi:10.1007/s40265-019-01155-4
21. Abu Samaan TM, Samec M, Liskova A, Kubatka P, Büsselberg D. Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer. Biomolecules. 2019;9(12):789. doi:10.3390/biom9120789
22. Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med. 2015;12(2):106-116. doi: 10.7497/j.issn.2095-3941.2015.0030
23. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. New England Journal of Medicine. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213
24. FDA U. FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments. FDA. Published April 22, 2020. Accessed June 1, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-triple-negative-breast-cancer-has-spread-not-responded-other-treatments
25. Meiyanto E, Putri H, Larasati YA, et al. Anti-Proliferative and Anti-Metastatic Potential of Curcumin Analogue, Pentagamavunon-1 (PGV-1), Toward Highly Metastatic Breast Cancer Cells in Correlation with ROS Generation. Advanced Pharmaceutical Bulletin. 2019; 9(3): 445-452. doi:10.15171/apb.2019.053
26. Lestari B, Nakamae I, Yoneda-Kato N, et al. Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Sci Rep. 2019; 9(1): 1-12. doi: 10.1038/s41598-019-51244-3
27. Meiyanto E, Husnaa U, Kastian RF, et al. The Target Differences of Anti-Tumorigenesis Potential of Curcumin and Its Analogues Against HER-2 Positive and Triple-Negative Breast Cancer Cells. Advanced Pharmaceutical Bulletin. 2021;11(1):188-196. doi: 10.34172/apb.2021.020.
28. Utomo RY, Wulandari F, Novitasari D, et al. Preparation and cytotoxic evaluation of PGV-1 derivative, CCA-1.1, as a new curcumin analog with improved-physicochemical and pharmacological properties. Advanced Pharmaceutical Bulletin, in Press.
29. Ahlina FN, Nugraheni N, Salsabila IA, Haryanti S, Da’i M, Meiyanto E. Revealing the Reversal Effect of Galangal (Alpinia galanga L.) Extract Against Oxidative Stress in Metastatic Breast Cancer Cells and Normal Fibroblast Cells Intended as a Co- Chemotherapeutic and Anti-Ageing Agent. Asian Pacific Journal of Cancer Prevention. 2020;21(1):107-117. doi:10.31557/APJCP.2020.21.1.107
30. Meiyanto E, Putri DDP, Susidarti RA, et al. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev. 2014;15(1):179-184.
31. Hermawan A, Fitriasari A, Junedi S, et al. PGV-0 and PGV-1 increased apoptosis induction of doxorubicin on MCF-7 breast cancer cells. Pharmacon. 2011;12(2):55-59.
32. Amalina ND, Nurhayati IP, Meiyanto E. Doxorubicin Induces Lamellipodia Formation and Cell Migration. Indonesian Journal of Cancer Chemoprevention. 2017; 8(2): 61–67.
33. Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-496. doi:10.3109/10715761003667554
34. Teppo H-R, Soini Y, Karihtala P. Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy. Oxid Med Cell Longev. 2017; 2017: 1485283. doi:10.1155/2017/1485283
35. Lee S, Lee J-S. Cellular senescence: a promising strategy for cancer therapy. BMB Rep. 2019;52(1):35-41. doi:10.5483/BMBRep.2019.52.1.294
36. Plesca D, Mazumder S, Almasan A. DNA Damage Response and Apoptosis. Methods Enzymol. 2008; 446: 107-122. doi:10.1016/S0076-6879(08)01606-6
37. Castedo M, Coquelle A, Vivet S, et al. Apoptosis regulation in tetraploid cancer cells. The EMBO Journal. 2006;25(11):2584-2595. doi: 10.1038/sj.emboj.7601127
38. Fragkos M, Beard P. Mitotic Catastrophe Occurs in the Absence of Apoptosis in p53-Null Cells with a Defective G1 Checkpoint. PLOS ONE. 2011;6(8): e22946. doi:10.1371/journal.pone.0022946
39. Gee M, Margaret M. Targeting the Mitotic Catastrophe Signaling Pathway in Cancer. Mediators of Inflammation. doi:https://doi.org/10.1155/2015/146282
40. Tanaka K, Goto H, Nishimura Y, Kasahara K, Mizoguchi A, Inagaki M. Tetraploidy in cancer and its possible link to aging. Cancer Sci. 2018;109(9):2632-2640. doi:10.1111/cas.13717
41. Eom Y-W, Kim MA, Park SS, et al. Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene. 2005;24(30):4765-4777. doi: 10.1038/sj.onc.1208627
42. Lee T, Lau T, Ng I. Doxorubicin-induced apoptosis and chemosensitivity in hepatoma cell lines. Cancer Chemother Pharmacol. 2002;49(1):78-86. doi:10.1007/s00280-001-0376-4
43. Hung J-Y, Wen C-W, Hsu Y-L, et al. Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells. Evidence-Based Complementary and Alternative Medicine. doi:https://doi.org/10.1155/2013/828143
44. Masgras I, Carrera S, Verdier PJ de, et al. Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21. J Biol Chem. 2012;287(13):9845-9854. doi:10.1074/jbc.M111.250357
45. Li H, Hu P, Wang Z, et al. Mitotic catastrophe and p53-dependent senescence induction in T-cell malignancies exposed to nonlethal dosage of GL-V9. Arch Toxicol. 2020;94(1):305-323. doi:10.1007/s00204-019-02623-2
46. Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nature Reviews Molecular Cell Biology. 2011;12(6):385-392. doi:10.1038/nrm3115
47. Bharadwaj D, Mandal M. Senescence in polyploid giant cancer cells: A road that leads to chemoresistance. Cytokine & Growth Factor Reviews. 2020;52:68-75. doi:10.1016/j.cytogfr.2019.11.002
48. Wang Q, Wu PC, Dong DZ, et al. Polyploidy road to therapy-induced cellular senescence and escape. International Journal of Cancer. 2013;132(7):1505-1515. doi:10.1002/ijc.27810
49. Bielak-Zmijewska A, Wnuk M, Przybylska D, et al. A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta. Biogerontology. 2014;15(1):47-64. doi:10.1007/s10522-013-9477-9
50. Beauséjour CM, Krtolica A, Galimi F, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22(16):4212-4222. doi:10.1093/emboj/cdg417
51. Elmore LW, Rehder CW, Di X, et al. Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J Biol Chem. 2002;277(38):35509-35515. doi:10.1074/jbc.M205477200
52. Yerlikaya A, Okur E, Ulukaya E. The p53-independent induction of apoptosis in breast cancer cells in response to proteasome inhibitor bortezomib. Tumour Biol. 2012;33(5):1385-1392. doi:10.1007/s13277-012-0386-3
53. Marinello J, Delcuratolo M, Capranico G. Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives. Int J Mol Sci. 2018;19(11). doi:10.3390/ijms19113480