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Published on: May 15, 2019
Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback
Aleksandra Pandyra1, Peter J Mullen2, Manpreet Kalkat1
1Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract:
New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.
Insights
This study found that combining statins with dipyridamole enhances their cancer-fighting ability in blood cancers like AML and multiple myeloma. This novel drug combination effectively targets cancer cells while sparing healthy ones.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Hematologic malignancies, including relapsed acute myelogenous leukemia (AML) and multiple myeloma, require novel therapeutic strategies.
- FDA-approved statins, targeting the mevalonate (MVA) pathway, have demonstrated tumor-selective apoptosis-inducing properties.
- Identifying synergistic drug combinations can enhance the efficacy of existing therapies.
Purpose of the Study:
- To identify FDA-approved drugs that synergize with statins to enhance their anticancer activity in hematologic malignancies.
- To investigate the mechanism by which drug combinations impact cancer cell apoptosis and tumor growth.
- To evaluate the potential of a novel drug combination for clinical application.
Main Methods:
- A drug screen of FDA-approved agents was performed to identify statin potentiators.
- The synergistic effects of the statin-dipyridamole combination were assessed in AML and multiple myeloma cell lines and patient samples.
- In vivo studies were conducted to evaluate the combination's effect on tumor growth.
- Mechanistic studies investigated the impact on the mevalonate pathway, including HMG-CoA reductase (HMGCR) and sterol regulatory element-binding transcription factor 2 (SREBP2) regulation.
Main Results:
- Dipyridamole was identified as a potent synergizer of statin anticancer activity.
- The statin-dipyridamole combination demonstrated synergistic apoptosis induction in hematologic cancer cells, sparing normal cells.
- This combination significantly reduced tumor growth in vivo.
- Dipyridamole was shown to inhibit the feedback upregulation of HMGCR and HMGCS1 by preventing SREBP2 cleavage.
Conclusions:
- Simultaneously targeting the MVA pathway and its feedback loop with statins and dipyridamole is a promising preclinical strategy for hematologic malignancies.
- This novel combination of FDA-approved drugs exhibits significant anticancer activity and warrants immediate clinical trial evaluation.
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