Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma

Abstract

Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou–Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.

Atorvastatin and Nitrofurantoin Repurposed in the Context of Breast Cancer and Neuroblastoma Cells

“…The Chou–Talalay method is based on the median effect equation, derived from the principle of the law of mass action. This unified theory encompasses the Michaelis–Menten, Hill, Henderson–Hasselbalch, and Scatchard equations in biochemistry and biophysics and provides a quantitative definition for additive effect (CI = 1), synergism (CI < 1), and antagonism (CI > 1) in drug combinations [ 25 ]. The fractional effect is a value between 0 and 1, where 0 means that the drug did not affect cell viability, and 1 means that the drug had a full effect in decreasing cell viability [ 19 , 26 ].…”

The Potential of Mushroom Extracts to Improve Chemotherapy Efficacy in Cancer Cells: A Systematic Review

“…Another significant limitation of this study is that although all the included studies described the combined use of mushroom extracts with chemotherapeutic agents as synergistic or potentiating, none of them carried out a comprehensive analysis of inhibitory concentrations. For example, there was no adequate investigation into combinations of chemotherapeutic drugs and mushroom extracts using increasing concentrations of both substances in a fixed ratio, as suggested by methods such as the Chou–Talalay approach [ 56 ] and as highlighted in the studies by Duarte et al [ 57 ] and Nunes et al [ 58 ], which used a bioinformatics tool.…”

Ivermectin Augments the Anti-Cancer Activity of Pitavastatin in Ovarian Cancer Cells

“…Here, we explored the potential for ivermectin to interact synergistically with pitavastatin and potentially reduce the dose of pitavastatin necessary to treat ovarian cancer. Previous work from Ricardo et al has shown a synergistic interaction between pitavastatin, paclitaxel, and ivermectin [ 30 ]. These authors found that these drugs synergistically decreased the viability of paclitaxel-resistant cells, using several different models to evaluate synergy.…”