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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Possible Selective Cytotoxicity of Vanadium Complex on Breast Cancer Cells Involving Pathophysiological Pathways

Author(s): Eman S. El-Shafey* and Eslam S. Elsherbiny

Volume 19, Issue 17, 2019

Page: [2130 - 2139] Pages: 10

DOI: 10.2174/1871520619666191024122117

Price: $65


Background: Triple-Negative Breast Cancers (TNBC) are among the most aggressive and therapyresistant breast tumors. Development of new treatment strategies that target pathways involved in cancer cells resistance is an attractive candidate to overcome therapeutic resistance.

Objective: To clarify the antitumor activity of [VO (bpy)2 Cl] Cl complex as a new therapeutic agent through studying the interplay between apoptosis, autophagy and notch signaling pathways.

Methods: Proliferation of MDA-MB-231 cells and IC50 value of the vanadium complex were assessed by MTT assay. Flow cytometry was utilized to detect cell cycle distribution, apoptosis assay, LC3 levels and Acid Vascular Organelles (AVOs). Caspase 3 levels were detected by ELISA. Changes in Notch1 gene expression were assessed by real-time PCR. AVOs qualitative detection was assessed by a fluorescence microscope.

Results: The growth of MDA-MB-231 cells was suppressed after treatment with [VO (bpy)2 Cl] Cl complex, in a dose-dependent manner. The affinity for apoptotic cell death induction was shown through the increase in the sub G0 peak, the percentage of early and late apoptotic phases, and the elevation in caspase 3 levels. The affinity for autophagic cell death induction was observed through the increase in the G0/G1 phase, G2/M arrest, the increase of AVOs red fluorescence and elevated LC3 levels. The affinity for notch pathway inhibition was shown through the suppression of Notch 1 gene expression.

Conclusion: [VO (bpy)2 Cl] Cl complex could be a promising candidate as therapeutic agent targeting different therapeutic targets including apoptosis, autophagy and notch signaling pathways.

Keywords: Apoptosis, autophagy, Notch1, vanadium complex, triple negative breast cancer, AVO.

Graphical Abstract
Uscanga-Perales, G.I.; Facio, S.K.S.; Ortiz-López, R. Triple negative breast cancer: Deciphering the biology and heterogeneity. Med. Univ., 2016, 18(71), 105-114.
Sharma, P. Biology and management of patients with triple-negative breast cancer. Oncologist, 2016, 21(9), 1050-1062.
[] [PMID: 27401886]
Wahba, H.A.; El-Hadaad, H.A. Current approaches in treatment of triple-negative breast cancer. Cancer Biol. Med., 2015, 12(2), 106-116.
[PMID: 26175926]
Ruiz-Casado, A.; Martín-Ruiz, A.; Pérez, L.M.; Provencio, M.; Fiuza-Luces, C.; Lucia, A. Exercise and the hallmarks of cancer. Trends Cancer, 2017, 3(6), 423-441.
[] [PMID: 28718417]
Pan, S.T.; Li, Z.L.; He, Z.X.; Qiu, J.X.; Zhou, S.F. Molecular mechanisms for tumour resistance to chemotherapy. Clin. Exp. Pharmacol. Physiol., 2016, 43(8), 723-737.
[] [PMID: 27097837]
El-Shafey, E.S.; Elsherbiny, E.S. Dual opposed survival-supporting and death-promoting roles of autophagy in cancer cells: A concise review. Curr. Chem. Biol., 2019, 13, 1.
Radogna, F.; Dicato, M.; Diederich, M. Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem. Pharmacol., 2015, 94(1), 1-11.
[] [PMID: 25562745]
Wong, R.S.Y. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30, 87.
[] [PMID: 21943236]
Larsen, B.D.; Sørensen, C.S. The caspase-activated DNase: Apoptosis and beyond. FEBS J., 2017, 284(8), 1160-1170.
[] [PMID: 27865056]
Ricci, M.S.; Zong, W.X. Chemotherapeutic approaches for targeting cell death pathways. Oncologist, 2006, 11(4), 342-357.
[] [PMID: 16614230]
Liu, Y.; Levine, B. Autosis and autophagic cell death: The dark side of autophagy. Cell Death Differ., 2015, 22(3), 367-376.
[] [PMID: 25257169]
Abraham, N.M.; Kirubel, M.M.; Abraham, D.A. Autophagy as a possible target for cancer therapy. J. Orthop. Oncol., 2017, 4(1), 124.
Mc Garty, T.P. Autophagy and Cancer, Springer; New York, Hiedelberg;. 2013.
Amaravadi, R.; Kimmelman, A.C.; White, E. Recent insights into the function of autophagy in cancer. Genes Dev., 2016, 30(17), 1913-1930.
[] [PMID: 27664235]
Gridley, T. Notch signaling in the vasculature. Curr. Top. Dev. Biol., 2010, 92(C), 277-309.
[] [PMID: 20816399]
Giancotti, F.G. Deregulation of cell signaling in cancer. FEBS Lett., 2014, 588(16), 2558-2570.
[] [PMID: 24561200]
Lamy, M.; Ferreira, A.; Sales Dias, J.; Braga, S.; Silva, G.; Barbas, A. Notch-out for breast cancer therapies. N. Biotechnol., 2017, 39, 215-221.
Yuan, X.; Wu, H.; Xu, H.; Xiong, H.; Chu, Q.; Yu, S.; Wu, G.S.; Wu, K. Notch signaling: An emerging therapeutic target for cancer treatment. Cancer Lett., 2015, 369(1), 20-27.
[] [PMID: 26341688]
Fazio, C.; Ricciardiello, L. Inflammation and Notch signaling: A crosstalk with opposite effects on tumorigenesis. Cell Death Dis., 2016, 7(12)e2515
[] [PMID: 27929540]
Kostova, I. Titanium and vanadium complexes as anticancer agents. Anticancer. Agents Med. Chem., 2009, 9(8), 827-842.
[] [PMID: 19538167]
Kowalski, S.; Hać, S.; Wyrzykowski, D.; Zauszkiewicz-Pawlak, A.; Inkielewicz-Stępniak, I. Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process. Oncotarget, 2017, 8(36), 60324-60341.
[] [PMID: 28947974]
Evangelou, A.M. Vanadium in cancer treatment. Crit. Rev. Oncol. Hematol., 2002, 42(3), 249-265.
[] [PMID: 12050018]
Sinha, A.; Banerjee, K.; Banerjee, A.; Das, S.; Choudhuri, S. Synthesis, characterization and biological evaluation of a novel vanadium complex as a possible anticancer agent. J. Organomet. Chem., 2014, 772-773, 34-41.
Roy, S.; Banerjee, S.; Chakraborty, T. Vanadium quercetin complex attenuates mammary cancer by regulating the P53, Akt/mTOR pathway and downregulates cellular proliferation correlated with increased apoptotic events. Biometals, 2018, 31(4), 647-671.
[] [PMID: 29855745]
Abdel-Mohsen, M.A.; Abdel Malak, C.A.; Abou Yossef, M.A.; El-Shafey, E.S. Antitumor activity of Copper (I)–Nicotinate complex and autophagy modulation in HCC1806 breast cancer cells. Anticancer. Agents Med. Chem., 2017, 17(11), 1526-1536.
Tanida, I.; Ueno, T.; Kominami, E. LC3 and autophagy. Methods Mol. Biol., 2008, 445, 77-88.
[] [PMID: 18425443]
Ahmed, H.H.; Toson, E.A.; El-Mezayen, H.A.; Rashed, L.A.; Elsherbiny, E.S. Role of mesenchymal stem cells versus angiotensin converting enzyme inhibitor in kidney repair. Nephrology (Carlton), 2017, 22(7), 531-540.
[] [PMID: 27162005]
Crowley, C.L.; Waterhouse, N. Detecting cleaved Caspase-3 in apoptotic cells by flow cytometry. Cold Spring Harb. Protoc., 2016, 2016, 11.
Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Natl. Rev., 2007, 8, 741-752.
Gump, J.M.; Thorburn, A. Autophagy and apoptosis: What is the connection? Trends Cell Biol., 2011, 21(7), 387-392.
[] [PMID: 21561772]
El-Shafey, E. Cytotoxic effect of doxorubicin and autophagy modulation on TNBC; Lambert Academic Publishing: Germany, 2019.
Chen, S.; Guan, J.L. Tumor-promoting and -suppressive roles of autophagy in the same mouse model of BrafV600E-driven lung cancer. Cancer Discov., 2013, 3(11), 1225-1227.
[] [PMID: 24203955]
Zheng, K.; He, Z.; Kitazato, K.; Wang, Y. Selective autophagy regulates cell cycle in cancer therapy. Theranostics, 2019, 9(1), 104-125.
[] [PMID: 30662557]
Tsapras, P.; Nezis, I.P. Caspase involvement in autophagy. Cell Death Differ., 2017, 24(8), 1369-1379.
[] [PMID: 28574508]
Lin, L.; Baehrecke, E.H. Autophagy, cell death, and cancer. Mol. Cell. Oncol., 2015, 2(3)e985913
[] [PMID: 27308466]
Wu, X.; Fleming, A.; Ricketts, T.; Pavel, M.; Virgin, H.; Menzies, F.M.; Rubinsztein, D.C. Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis. Nat. Commun., 2016, 7, 10533.
[] [PMID: 26837467]
Li, L.; Zhao, F.; Lu, J.; Li, T.; Yang, H.; Wu, C.; Liu, Y. Notch-1 signaling promotes the malignant features of human breast cancer through NF-κB activation. PLoS One, 2014, 9(4)e95912
[] [PMID: 24760075]
Li, L.; Tang, P.; Li, S.; Qin, X.; Yang, H.; Wu, C.; Liu, Y. Notch signaling pathway networks in cancer metastasis: A new target for cancer therapy. Med. Oncol., 2017, 34(10), 180.
[] [PMID: 28918490]
Zhou, Y.F.; Sun, Q.; Zhang, Y.J.; Wang, G.M.; He, B.; Qi, T.; Zhou, Y.; Li, X.W.; Li, S.; He, L. Targeted inhibition of Notch1 gene enhances the killing effects of paclitaxel on triple negative breast cancer cells. Asian Pac. J. Trop. Med., 2017, 10(2), 179-183.
[] [PMID: 28237486]
Zhang, J.X.; Han, Y.P.; Bai, C.; Li, Q. Notch1/3 and p53/p21 are a potential therapeutic target for APS-induced apoptosis in non-small cell lung carcinoma cell lines. Int. J. Clin. Exp. Med., 2015, 8(8), 12539-12547.
[PMID: 26550164]
Ozpolat, B.; Alpay, N.; Lopez-Berestein, G. Induction of Autophagic Cell Death by Targeting Bcl-2 as a Novel Therapeutic Strategy in Breast Cancer.In: Targeting New Pathways and Cell Death in Breast Cancer; InTech: China, 2012.
Ryter, S.W.; Mizumura, K.; Choi, A.M.K. The impact of autophagy on cell death modalities. Int. J. Cell Biol., 2014, 2014502676
[] [PMID: 24639873]
Su, Z.; Yang, Z.; Xu, Y.; Chen, Y.; Yu, Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol. Cancer, 2015, 14, 48.
[] [PMID: 25743109]
Huang, Y.; Liu, F.; Zhang, F.; Liu, P.; Xu, T.; Ding, W. Vanadium (IV)-chlorodipicolinate alleviates hepatic lipid accumulation by inducing autophagy via the LKB1/AMPK signaling pathway in vitro and in vivo. J. Inorg. Biochem., 2018, 183, 66-76.
Abdel-Mohsen, M.A.; Abdel Malak, C.A.; El-Shafey, E.S. Influence of copper (I) nicotinate complex and autophagy modulation on doxorubicin-induced cytotoxicity in HCC1806 breast cancer cells. Adv. Med. Sci., 2019, 64(1), 202-209.
[] [PMID: 30798072]
El-Shafey, E.S. Assessment of the effect of copper complex on autophagy in TNBC cells; Lambert Academic Publishing: Germany, 2018.
Fassl, A.; Tagscherer, K.E.; Richter, J.; De-Castro Arce, J.; Savini, C.; Rösl, F.; Roth, W.; Roth, W. Inhibition of notch1 signaling overcomes resistance to the death ligand trail by specificity protein 1-dependent upregulation of death receptor 5. Cell Death Dis., 2015, 6e, 1921.
[] [PMID: 26469969]

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