Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein

• Published in: Journal of inorganic biochemistry Vol. 191; pp. 29 - 39
• Main Authors: Kawahara, Brian, Ramadoss, Sivakumar, Chaudhuri, Gautam, Janzen, Carla, Sen, Suvajit, Mascharak, Pradip K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2019
• Subjects: Antineoplastic Agents - pharmacology; Carbon monoxide; Carbon Monoxide - pharmacology; Cell Line, Tumor; Cell Nucleus - metabolism; Cisplatin - pharmacology; Cisplatin-resistance; Cystathionine beta-Synthase - antagonists & inhibitors; Cystathionine β-synthase; Cysteine - metabolism; Drug Resistance, Neoplasm; Female; Glutathione; Glutathione - metabolism; Humans; Metallothionein; Metallothionein - metabolism; Ovarian cancer; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Carbon monoxide; Cystathionine β-synthase; Cisplatin-resistance; Metallothionein; Ovarian cancer; Glutathione
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2018.11.003

Cisplatin resistance remains a major impediment to effective treatment of ovarian cancer. Despite initial platinum 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 cells 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-phosphaadamantane) 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 expression 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. Light-controlled delivery of CO from a photoactive metal carbonyl complex (photoCORM) lowers levels of glutathione and nuclear metallothionein via inhibition of cystathionine β-synthase. These steps sensitize cisplatin-resistant ovarian cancer cells toward cisplatin. [Display omitted] •A designed photoactive CO-releasing molecule (photoCORM) has been utilized to deliver CO to cancer cells.•CO inhibits cystathionine-β-synthase (CBS) in ovarian cancer cells.•CBS modulates the levels of nuclear metallothionein (MT) and total glutathione (GSH).•Modulation of MT and GSH by CO decreases cisplatin resistance.•Delivery of CO drastically improves efficacy of cisplatin against ovarian cancer.