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    Contents lists available at ScienceDirect
    Journal of Inorganic Biochemistry
    journal homepage:
    Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein 
    Brian Kawaharaa, Sivakumar Ramadossb, Gautam Chaudhurib, Carla Janzenb, Suvajit Senb, , Pradip K. Mascharaka, a Contribution from Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, United States of America b Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States of America
    Carbon monoxide
    Ovarian cancer
    Cystathionine β-synthase
    Cisplatin resistance remains a major impediment to effective treatment of ovarian cancer. Despite initial pla-tinum responsiveness, thiol-containing peptides and proteins, glutathione (GSH) and metallothionein (MT), bind and inactivate cisplatin in cancer cells. Indeed, high levels of GSH and MT in ovarian cancers impart cisplatin resistance and are predictive of poor prognosis. Cystathionine β-synthase (CBS), an enzyme involved in sulfur metabolism, is overexpressed in ovarian cancer tissues and is itself associated with cisplatin resistance. Treatment with exogenous carbon monoxide (CO), a known inhibitor of CBS, may mitigate cisplatin resistance in ovarian cancer Trametinib by attenuation of GSH and MT levels. Using a photo-activated CO-releasing molecule (photoCORM), [Mn(CO)3(phen)(PTA)]CF3SO3 (phen = 1,10-phenanthroline, PTA = 1,3,5-triza-7-phosphaada-mantane) we assessed the ability of CO to sensitize established cisplatin-resistant ovarian cancer cell lines to cisplatin. Cisplatin-resistant cells, treated with both cisplatin and CO, exhibited significantly lower cell viability and increased poly (ADP-ribose) polymerase (PARP) cleavage versus those treated with cisplatin alone. These cisplatin-resistant cell lines overexpressed CBS and had increased steady state levels of GSH and expression of nuclear MT. Both CO treatment and lentiviral-mediated silencing of CBS attenuated GSH and nuclear MT ex-pression in cisplatin resistant cells. We have demonstrated that CO, delivered from a photoCORM, sensitizes established cisplatin-resistant cell lines to cisplatin. Furthermore, we have presented strong evidence that the effects of CO in circumventing chemotherapeutic drug resistance is at least in part mediated by the inactivation of endogenous CBS.
    1. Introduction
    Ovarian cancer is the fifth most prevalent and the most lethal gy-necological cancer in the United States [1]. The overall 5-year survival rate for advanced ovarian cancer patients is only ~40% and has re-mained largely static over the past 20 years [2]. The current standard of care includes cytoreductive surgery and combination platinum/taxane chemotherapy [3]. However, ~90% of ovarian cancer deaths are caused by chemotherapeutic resistance and metastasis [4]. Clearly there is an unmet need for treatment modalities to mitigate che-motherapeutic resistance.
    Cisplatin is one of the most widely used and effective anti-cancer drugs. In addition to ovarian cancer, it is the standard of care for other solid cancers of the head and neck, bowel and colon, cervix and lung.
    By localizing to the nucleus and binding to DNA, cisplatin gives rise to intrastrand DNA adducts and triggers G2 cell cycle arrest and sub-sequent apoptosis. The effectiveness of cisplatin, however, is limited by the high incidences of drug resistance [5,6]. In the cases of colorectal, lung and prostate cancers, intrinsic resistance is common [5]. In ovarian cancer, however, resistance is mainly acquired after initial treatment and response to cisplatin therapy [5]. Understanding the cellular changes that occur in the development of cisplatin resistance will help in developing more effective means of circumventing cisplatin resistance in ovarian cancer.