Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

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.

Cross-resistance of cisplatin selected cells to anti-microtubule agents: Role of general survival mechanisms

“…1 B). Cell elongation in cisplatin-resistant cells have been observed previously [33] . It is possible that the cell elongation could be due to microtubule involvement.…”

The involvement of small heat shock protein in chemoresistance in ovarian cancer - in vitro study

“…On the other hand, the SKOV3 cell line is derived from cells of a patient diagnosed with high-grade serous ovarian cancer with intrinsic resistance mechanisms to treatment. For over six months, we generated the cisplatin-resistant variants cell lines (named as follows: A2780 CDDP and SKOV3 CDDP), which were already described and characterized in a previous study (Michalak et al, 2020[ 37 ]). Briefly, we adapted cells to the concentration of cisplatin starting from 200 ng/ml to 1 µg/ml of cell culture medium.…”

“…In this preliminary study, we have shown novel information about the potential involvement of small HSPs in the chemoresistance of OvCa, using in vitro model of two OvCa cell lines: A2780 and SKOV3 (sensitive and resistant to cisplatin), representing endometrioid and serous OvCa, respectively. To exclude the genetic drift during the prolonged culture to obtain stable resistance to cisplatin phenotype of OvCa cell lines, we used as control parallel cultured cells not exposed to CDDP (Michalak et al, 2020[ 37 ]). In the A2780 cell line, the expression of HSPB5 and HSPB6 was decreased in chemoresistant cells, while the expression of HSPB8 remained unchanged.…”

“…From each of these cell lines were generated cisplatin-resistant cell variants named as follows: A2780 CDDP and SKOV3 CDDP. The cell culture conditions and derivation of cisplatin-resistant cell lines were conducted and confirmed as previously described (Michalak et al, 2020[ 37 ]).…”

Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer

“…Another strategy to overcome deactivation is to combine cisplatin with other anticancer agents such as paclitaxel, 5‐fluorouracil, gemcitabine or ruthenium complexes. [ 13–16 ] Mixtures of anticancer agents possess multiple targets and actions; this strategy strengthens the therapeutic effects via the different anticancer mechanisms of the different agents. [ 14 ] A third strategy to overcome deactivation is to use nanocarriers for the delivery of cisplatin.…”