Interaction of Adenosine, Modified Using Carborane Clusters, with Ovarian Cancer Cells: A New Anticancer Approach against Chemoresistance

SIMPLE SUMMARY: Ovarian cancer has the highest mortality rate among gynecological malignancies and is the second most commonly diagnosed gynecological cancer. Acquired resistance to platinum therapy remains a major problem in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes and antimetabolite activity of nucleoside derivatives, we designed and synthesized the adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence cisplatin-resistance of cancer cells. The iron-containing conjugate of metallacarborane and adenosine sensitized resistant cancer cells and highly resistant multicellular cancer spheroids to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. The presence of nucleosides in the structure of the conjugates was revealed to be indispensable for protecting cells against the development of cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term-cultures. The findings indicate that adenine nucleoside modified with metallacarboranes may help sensitize ovarian cancer cells to chemotherapeutic agents in combination therapy. ABSTRACT: Platinum compounds remain the first-line drugs for the treatment of most lethal gynecological malignancies and ovarian cancers. Acquired platinum resistance remains a major challenge in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes modifier and the significant role of nucleoside derivatives as anticancer antimetabolites, we designed and synthesized a set of adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence the cisplatin sensitivity of ovarian cancer cells. Adherent cultures of ovarian carcinoma cell lines and multicellular spheroids, ranging from sensitive to highly resistant including experimental cell lines “not responding” to platinum drugs were used. Iron-containing metallacarborane conjugates showed the best anticancer activity, especially against resistant cells. Compound modified at the C2′ nucleoside position showed the best activity in resistant cancer cells and highly resistant cancer spheroids exposed to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. Moreover, it showed high cellular accumulation and did not induce cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term cultures. The reference nido-carborane derivative (no metal ions) and unmodified nucleosides were not as effective. These findings indicate that metallacarborane modification of adenosine may sensitize ovarian cancer cells to cisplatin in combination treatment.