Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Mariana Nunes, Miguel Henriques Abreu, Carla Bartosch, Sara Ricardo, Mariana Nunes, Miguel Henriques Abreu, Carla Bartosch, Sara Ricardo

Abstract

The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.

Keywords: chemoresistance; drug repurposing; ex vivo cultures; ovarian cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of action of non-oncological drugs in ovarian cancer (OC). Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) leading to the blocking of cholesterol biosynthetic pathway though a mevalonate-dependent mechanism. Moreover, statins can block drug efflux pumps by a mevalonate-independent mechanism. Bisphosphonates block farnesyl pyrophosphate synthase, located downstream HMGCR, leading to the impairment of cholesterol biosynthesis. Metformin inhibits insulin signals and glucose synthesis via respiratory-chain complex I blockage. Ritonavir is a protease inhibitor that inhibits the production of phosphorylated protein kinase B (AKT) leading to the impairment of phosphatidylinositol 3-kinases (PI3K)-Akt pathway. Itraconazole can inhibit Hedgehog, mammalian target of rapamycin (mTOR), and Wnt signalling pathway. Moreover, itraconazole can inhibit angiogenesis and lymphangiogenesis, and promote the overexpression of P-glycoprotein. Ivermectin interferes with several cellular mechanisms, including multidrug resistance proteins (MDR) inhibition, Akt/mTOR, and Wnt signalling pathways modulation, p21–activated kinase (PAK-1) and yes-associated protein 1 (YAP1). Moreover, ivermectin promotes the increase of intracellular reactive oxygen species (ROS) levels leading to the downregulation of stemness genes. Adenosine diphosphate (ADP); adenosine monophosphate (AMP); adenosine triphosphate (ATP); 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA).
Figure 2
Figure 2
Establishment of ex vivo models from ascitic fluid-derived cancer cells to perform drug efficacy tests. Combination of drug repurposing (e.g., pitavastatin, metformin, bisphosphonates, ivermectin, itraconazole and ritonavir) with conventional chemotherapy (e.g., carboplatin and paclitaxel) may have the benefits of increased efficacy and has potential to decrease the risk of therapeutic failure. The effectiveness of drug repurposing approaches to target or sensitize chemoresistant cells to conventional chemotherapy can be validate in established ex vivo models. A schematic diagram demonstrating the conventional chemotherapy in combination with compounds of drug repurposing that can directly target the chemoresistant cell and tumour loses its ability to generate new cancer cells, or sensitize chemoresistant cells in order to disrupt the stemness and make them more sensitive to conventional chemotherapy.

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