Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion

Abstract

Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently (>75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance to therapy have proven challenging. Despite advances in OC diagnosis and treatment, approximately 85% of patients will experience relapse, mainly due to chemoresistance. The latter is attributed to alterations in the cancer cells and is also mediated by tumor microenvironment (TME). Recently, we reported the synthesis of a platinum (IV) prodrug that exhibits equal potency toward platinum-sensitive and resistant OC cell lines. Here, we investigated the effect of TME on platinum sensitivity. Co-culture of OC cells with murine or human mesenchymal stem cells (MS-5 and HS-5, respectively) rendered them resistant to chemotherapeutic agents, including platinum, paclitaxel and colchicine. Platinum resistance was also conferred by co-culture with differentiated murine adipocyte progenitor cells. Exposure of OC cells to chemotherapeutic agents resulted in activation of phospho-ERK1/2. Co-culture with MS-5, which conferred drug resistance, was accompanied by blockage of phospho-ERK1/2 activation. The flavonoids fisetin and quercetin were active in restoring ERK phosphorylation, as well as sensitivity to platinum compounds. Exposure of OC cells to cobimetinib—a MEK1 inhibitor that also inhibits extracellular signal-regulated kinase (ERK) phosphorylation—which resulted in reduced sensitivity to the platinum compound. This suggests that ERK activity is involved in mediating the function of flavonoids in restoring platinum sensitivity to OC co-cultured with cellular components of the TME. Our data show the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcome TME-mediated platinum drug resistance.

2-Hydroxyestradiol Overcomes Mesenchymal Stem Cells-Mediated Platinum Chemoresistance in Ovarian Cancer Cells in an ERK-Independent Fashion

“…Previously, we synthesized a bis-octanoatoplatinum (IV) complex (RJY13), a cisplatin derivative with octanoate as an axial ligand, which exhibited a strong anti-proliferative effect on the cisplatin-resistant and cisplatin-sensitive ovarian cells [ 26 ]. Moreover, we demonstrated that direct co-culture of OC cells with mesenchymal stem cells (MSC) conferred chemoresistance to the platinum compound (RJY13) that was accompanied by blocking of ERK1/2 activation [ 15 ]. Our previous findings demonstrated that the flavonoid fisetin restored platinum drug sensitivity to OC cells co-cultured with MSC accompanied by re-activation of ERK1/2 [ 15 ].…”

“…Malignant ascites acts as a reservoir for a complex mixture of metabolites, soluble factors, and cellular compartments, providing a pro-inflammatory and tumor-promoting microenvironment for the OC cells that could also be associated with chemoresistance [ 6 , 10 , 11 , 12 , 13 , 14 ]. Previously, we demonstrated that direct co-culture of OC with mesenchymal stem cells (MSC) conferred chemoresistance to therapeutic agents including paclitaxel, colchicine, and platinum compounds, accompanied by blocking of ERK1/2 activation [ 15 ]. Additionally, we demonstrated that the combination of a platinum drug with fisetin and other flavonoids restored platinum drug sensitivity to OC cells co-cultured with MSC accompanied by re-activation of ERK1/2 [ 15 ].…”

“…Previously, we demonstrated that direct co-culture of OC with mesenchymal stem cells (MSC) conferred chemoresistance to therapeutic agents including paclitaxel, colchicine, and platinum compounds, accompanied by blocking of ERK1/2 activation [ 15 ]. Additionally, we demonstrated that the combination of a platinum drug with fisetin and other flavonoids restored platinum drug sensitivity to OC cells co-cultured with MSC accompanied by re-activation of ERK1/2 [ 15 ].…”

“…Our findings that chemoresistance is promoted by direct co-culture of MSC with OC cells were not limited to platinum compounds but included other chemotherapeutics such as paclitaxel and colchicine [ 15 ], arguing that other transporters such as ABC transporters might be involved.…”

Detailed Molecular Mechanism and Potential Drugs for COL1A1 in Carboplatin-Resistant Ovarian Cancer

“…To identify whether ZINC000085537017 or quercetin affected carboplatin sensitization in OV, first, carboplatin-resistant cell lines (A2780-carboplatin and SKOV3-carboplatin) were assayed for cell viability after treatment with a concentration gradient of ZINC000085537017 or quercetin (0, 0.01, 0.1, 1, 10, 100 μM) for 24 h. As shown in Figures S3A–B and S3C–D , 0.01–1.00 μM ZINC000085537017 and 0.01–10.0 μM quercetin did not significantly inhibit cell growth, but 10–100 μM ZINC000085537017 and 100 μM quercetin significantly reduced cell viability ( p < 0.05). Then, based on previous research ( 22 , 23 ), we selected 1 μM ZINC000085537017 and 10 μM quercetin for subsequent studies. Second, we calculated the IC 50 values for carboplatin treatment for 48 h. The IC 50 values of A2780, A2780-carboplatin, SKOV3, and SKOV3-carboplatin were 19.03 μM (7.066 μg/mL), 91.28 μM (33.89 μg/mL), 15.18 μM (5.635 μg/mL), and 68.96 μM (25.6 μg/mL), respectively.…”