2Pamukkale University, Seed Breeding and Genetic Application and Research Centre, Denizli-Turkey
3Department of Biomedical Engineering, Pamukkale University, Faculty of Technology, Denizli-Turkey
4Department of Molecular Biology and Genetics, Abdullah Gül University, Faculty of Life and Natural Sciences, Kayseri-Turkey DOI : 10.5505/tjo.2020.2380 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.