Title:Anti-carcinogenic Effect of Cathepsin K Inhibitor, Odanacatib with a Low Dose of Cisplatin Against Human Breast Carcinoma MCF-7 and MDA-MB231 Cells
Volume: 17
Issue: 2
Author(s): Yaongamphi Vashum, Amuthavalli Kottaiswamy, Tholcopiyan Loganathan, Fathima B. Sheriff and Shila Samuel*
Affiliation:
- Department of Biochemistry, VRR Institute of Biomedical Science (Affiliated to University of Madras), Chennai- 600056, Tamilnadu,India
Keywords:
Breast cancer, chemoresistance, cathepsin K, odanacatib, cisplatin, synergism, apoptosis.
Abstract:
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 issues,
the present study has established the use of cathepsin k (CTSK) inhibitor as a potent chemosensitizer.
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 the 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) induced
a synergistic cytotoxic effect in different breast cancer cells. Diminished expression of Bcl-2
and increased expression of Bax aroused the cytochrome release, that triggered caspase-9 and -3 activation
in the combinatorial group. ODN with a lower dose of cisplatin significantly inhibited the
protein expression of novel chemoresistant factors such as STAT3, NFκB and IL-6.
Conclusion: This study highlights the potential effects of the combination of ODN with a reduced
dose of cisplatin on improving the growth inhibition and apoptosis-inducing effect on breast cancer
cells via combined inhibition of NF-κB-induced IL-6 and STAT3 activation. The study result
suggests that the further development of this novel inhibitor in combination with a low dose of standard
cisplatin-based chemotherapy may contribute to an alternative treatment option for certain
cancers.
