Abstract
Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.
Highlights
Despite developing new therapeutic strategies and extensive knowledge about tumor biology, ovarian cancer (OvCa) remains a leading cause of mortality among gynecologic malignancies; asymptomatic early stages and lack of ambiguous biomarkers enabling detection of the disease lead to late diagnosis, mostly at stage III and IV [1,2]
The intrinsic and acquired resistance to platinum-based chemotherapy is the main reason for OvCa treatment failure [6,7]
Our experiments provided interesting data regarding the activity of SAL and its derivatives against platinum resistance developed in OvCa cell lines in vitro
Summary
Despite developing new therapeutic strategies and extensive knowledge about tumor biology, ovarian cancer (OvCa) remains a leading cause of mortality among gynecologic malignancies; asymptomatic early stages and lack of ambiguous biomarkers enabling detection of the disease lead to late diagnosis, mostly at stage III and IV [1,2]. Most of the patients respond well to radical surgery and either neoadjuvant or adjuvant chemotherapy. 75% of patients develop recurrence [4]. Molecules 2020, 25, 537 earlier than six months after completion of the initial platinum-based therapy [5]. This state is called platinum-resistance in opposition to platinum-sensitive patients who develop recurrence more than six months after completion of the initial therapy. The intrinsic and acquired resistance to platinum-based chemotherapy is the main reason for OvCa treatment failure [6,7]
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