Apatinib sensitizes human breast cancer cells against navitoclax and venetoclax despite up-regulated bcl-2 and mcl-1 gene expressions

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Kavakcioglu Yardimci B., Ozgun Acar O., SEMİZ A., ŞEN A.

Turk Onkoloji Dergisi, vol.36, no.1, pp.8-16, 2021 (ESCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 36 Issue: 1
  • Publication Date: 2021
  • Doi Number: 10.5505/tjo.2020.2380
  • Journal Name: Turk Onkoloji Dergisi
  • Journal Indexes: Emerging Sources Citation Index (ESCI), Scopus, Academic Search Premier, CINAHL, EMBASE, TR DİZİN (ULAKBİM)
  • Page Numbers: pp.8-16
  • Keywords: Apatinib, Apoptosis, Breast adenocarcinoma, Cytotoxicity, Navitoclax, Venetoclax
  • Abdullah Gül University Affiliated: No


© 2021, Turkish Society for Radiation Oncology.OBJECTIVE Defects in apoptotic cell death which restrict the success of conventional cytotoxic therapies have pivotal roles in a number of pathological conditions including cancer. However, a novel drug class targeting pro-survival Bcl-2 protein family members has been developed with the understanding of the structures and interactions of Bcl-2 proteins. Within this new class, Bcl-2/Bcl-xL inhibitor Navitoclax and Bcl-2 specific inhibitor Venetoclax have been shown to demonstrate strong anticancer activities on several types of cancers. But their low affinity to other anti-apoptotic proteins limits their clinical usage. Here, we investigated the cytotoxic and apoptotic effects of Navitoclax/Venetoclax and their combinations with specific tyrosine kinase inhibitor Apatinib on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines. METHODS MTT assay was used for the evaluation of the inhibition of cancer cell proliferation. ELISA test and Quantitative real-time PCR assay was performed to determine the role of caspase-3, Bak, Bax, Bcl-2, Bcl-xL and Mcl-1 proteins in the inhibition of cell proliferation triggered by the tested agents. RESULTS We found that aggressive MDA-MB-231 cell line was more sensitive to all tested agents. Apatinib significantly enhanced Navitoclax/Venetoclax mediated inhibition of cell viability in both cancer cell lines despite up-regulation in the expression levels of Bcl-2 and Mcl-1 genes. We further demonstrated significant Bak/Bax and caspase-3 expression in less aggressive MCF-7 cells. CONCLUSION Our findings have impacts on Navitoclax/Venetoclax plus Apatinib based therapy for breast adenocarcinoma. On the other hand, further studies should be conducted to elucidate the mechanisms underlying synergistic effects of Navitoclax/Venetoclax plus Apatinib combinations.