Abstract
In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson’s correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.
Highlights
Published: 21 January 2022The recent emergence of drugs that target specific molecules and antibodies for ovarian cancer treatment has immensely improved the therapeutic outcomes [1]; a paradigm shift from treatment to prevention is required in the future
To conduct an efficient clinical trial, in this study, we aimed to understand the details of the mode of action of statins, establish biomarkers to select patients who would respond to statins, confirm that statins would respond to clinical samples, ensure the safety of administration, and examine the synergistic effects of combination therapy to be tested in clinical trials
We previously showed that statins have a proliferative and tumor-suppressive effect on ovarian cancer cells by inhibiting the mevalonate pathway, the farnesylation and geranylgeranylation pathways, which are involved in protein prenylation [14]
Summary
Published: 21 January 2022The recent emergence of drugs that target specific molecules and antibodies for ovarian cancer treatment has immensely improved the therapeutic outcomes [1]; a paradigm shift from treatment to prevention is required in the future. The probability of drug approval from the seeds is extremely low; novel drug discovery methods are needed [2,3]. One solution to this problem is drug repurposing. It involves the use of an existing drug for a disease for which it was not developed. The safety of these drugs has already been confirmed in humans. As a drug repurposed for ovarian cancer, statins, which are used to treat dyslipidemia, have been investigated in epidemiological studies, basic research, and clinical trials [7]. Statins, used worldwide for dyslipidemia treatment, reduce blood cholesterol levels by inhibiting hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase, which is located upstream of the mevalonate pathway that biosynthesizes cholesterol from acetyl coenzyme A [8]
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