Background:
A cross-linking agent commonly used for cancer chemotherapy is a platinum compound such as
cisplatin. However, with the acquisition of cellular drug resistance and adverse side effects, the potency of cisplatin is
therefore, often tempered. To overcome these, the present study has established the use of cathepsin k (CTSK) inhibitor as
a potent chemo sensitizer.
Methods:
The cytotoxic effect of cisplatin and odanacatib (ODN) on two different breast cancer patient-derived cell lines,
MDA-MB-231 and MCF-7, was assessed by MTT-based colorimetric assay. The drug interaction coefficient CDI was
used to evaluate the synergistically inhibitory impact of the drug combination and immunoblot was used to examine
protein expression of certain proteins responsible for cell survival and the mechanism of apoptosis.
Results:
In this study, we found that IC50 of ODN in combination with cisplatin (half of IC25) induces a synergistic
cytotoxic effect in different breast cancer cells. Diminished expression of Bcl-2 and increased expression of Bax aroused
the cytochrome release, that triggers caspase-9 and -3 activation in the combinatorial group. ODN with lower dose of
cisplatin significantly inhibits the protein expression of novel chemoresistant factors such as STAT3, NFҡB and IL-6.
Conclusion:
This study highlights the potential effects of the combination of ODN with reduced dose of cisplatin on
improving the growth inhibition and apoptosis-inducing effect on breast cancer cells via combined inhibition of NF-κBinduced IL-6 and STAT3 activation.The study result suggests that the further development of this novel inhibitor
combination with low dose of standard cisplatin-based chemotherapy may contribute to alternative treatment option for
certain cancers.
Reprogramming ovarian and breast cancer cells into non-cancerous cells by low-dose metformin or SN-38 through FOXO3 activation
