Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate

Abstract

Cisplatin is used in treatment of several types of cancer, including epithelial ovarian carcinoma (EOC). In order to mimic clinical treatment and to investigate longterm effects of cisplatin in surviving cancer cells, two EOC cell lines were repeatedly treated with low doses. In the SKOV-3 cell line originating from malignant ascites, but not in A2780 cells from a primary tumor, this led to emergence of a stable population (SKOV-3-R) which in the absence of cisplatin showed increased motility, epithelial-mesenchymal transition (EMT) and expression of cancer stem cell markers CD117, CD44 and ALDH1. Accordingly, the cells formed self-renewing spheres in serum-free stem cell medium. Despite upregulation of mitochondrial mass and cytochrome c, and no upregulation of Bcl-2/Bcl-xL, SKOV-3-R were multiresistant to antineoplastic drugs. Cancer stem cells, or tumor-initiating cells (TICs) are highly chemoresistant and are believed to cause relapse into disseminated and resistant EOC. Our second aim was therefore to target resistance in these TIC-like cells. Resistance could be correlated with upregulation of hexokinase-II and VDAC, which are known to form a survival-promoting mitochondrial complex. The cells were thus sensitive to 3-bromopyruvate, which dissociates hexokinase-II from this complex, and were particularly sensitive to combination treatment with cisplatin at doses down to 0.1 x IC₅₀. 3-bromopyruvate might thus be of use in targeting the especially aggressive TIC populations.

Keywords: :

• cisplatin
• epithelial-mesenchymal transition
• tumor-initiating cells
• chemoresistance
• hexokinase
• 3-bromopyruvate

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful for the funding from the Swedish Cancer Society, the Swedish Research Council, the Radiumhemmet Research Funds, and the Olle Engkvist Foundation. We thank B.Sc. Oskar Rosencrantz for fruitful discussions.