Natural compounds in combination with platinum drugs administered to ovarian cancer models towards synergistic outcomes

Abstract

Ovarian cancer is known as one of the dreaded diseases due to its low five years’ survival, acquired drug resistance and recurrence. It is treated mainly by platinum drugs given alone or in combination with paclitaxel. However, problems of drug resistance that is often acquired still remain. While resistance to platinum drugs at the molecular level can be due to overexpression of nuclear factor kappa B (NF-κB) and protein kinase B (AKT/PKB) pathways, it is believed that phytochemicals and other natural compounds can inhibit expression of NF-κB and AKT/PKB. This study aimed to apply binary combinations of platinum drugs cisplatin and oxaliplatin with natural compounds mycophenolic acid, honokiol, cholecalciferol and 6-shogaol to four ovarian cancer cell lines: A2780, A2780cisR, A2780ZD0473R and SKOV-3 towards overcoming drug resistance. IC50 values of compounds were first determined before the combination studies. Studies on DNA damage, cellular platinum accumulation and platinum-DNA binding were carried out. Proteomic study has been performed aiming to determine key proteins associated with drug resistance. Mycophenolic acid (IC50: 1.34-7.83 μM) and 6-shogaol (IC50: 6.79-10.20 μM) showed significant activity against ovarian cancer cell lines compared to cisplatin (IC50: 1.18-9.02 μM). 6-shogaol showed synergism in combination with cisplatin and oxaliplatin when administered as a bolus 0/0h and with 0/4 h sequence against A2780, A2780cisR and A2780ZD0473R cell lines. Honokiol alone and in combination with cisplatin caused significant DNA damage in the parent A2780 cell line whereas cholecalciferol did the same to cisplatin-resistant A2780cisR cell line. Concurrent administration of cisplatin and 6-shogaol produced higher cellular platinum accumulation and three times greater platinum-DNA binding than cisplatin in the parent ovarian A2780 cell line. Although (0/0 h) combination of honokiol and cisplatin produced a lower cellular accumulation of platinum, it resulted in greater platinum-DNA binding. Cholecalciferol and 6-shogaol in combination with cisplatin also produced increased platinum-DNA binding in the A2780cisR cell line. Proteomic studies have been performed to explore the proteins involved with drug-resistance in cisplatin-resistant A2780cisR and picoplatin-resistant A2780ZD0473R cell lines. Nineteen proteins were found to be significantly expressed in 23 different spots in untreated A2780cisR and A2780ZD0473R cell lines compared to the expression level observed in the untreated parent A2780 cell line. Selected synergistic combinations of platinum drugs and natural compounds were associated with reduced expression of anti-apoptotic proteins and heightened expression of the pro-apoptotic proteins towards overcoming chemoresistance. 6-shogaol in combination with cisplatin and oxaliplatin had the ability to combat platinum chemoresistance by downregulating the expression of the anti-apoptotic proteins and increasing the expression of the pro-apoptotic proteins in ovarian A2780cisR and A2780ZD0473R cell lines. In summary, ginger derived phytochemical, 6-shogaol alone and in combination with cisplatin and oxaliplatin showed significant cytotoxicity against ovarian cancer tumour models. Therefore, 6-shogaol could be a prospective candidate for combination therapy to manage ovarian cancer in future.