Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy
Abstract
:Simple Summary
Abstract
1. Cellular Metabolism of Normal and Cancerous Cells
1.1. Cellular Metabolism in Normal Non-Cancerous Cells
1.2. The Role of Metabolism in Tumorigenesis
2. The Mevalonate Pathway
2.1. Regulation of Metabolic Reprograming by Tumor Suppressor and Proto-Oncogenic Genes
2.2. Mevalonate Pathway
2.3. Mevalonate Pathway in the Tumor Microenvironment
2.4. The Mevalonate Pathway and Therapy Resistance
3. Targeting the Mevalonate Pathway
3.1. Statin Drugs
3.2. Pre-Clinical In Vitro and In Vivo Studies
3.3. Statins and Cancer Incidence and Mortality
3.4. Statins and Current Clinical Trials
4. Considerations When Targeting Cancer Metabolism with Statins
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Statin | Statin Type | Side Ring | Solubility | Transport | Half-Life (h) | Dose (mg/day) | Optimal Dosing Time |
---|---|---|---|---|---|---|---|
Atorvastatin | II | Pyrrole | Lipophilic | Passive | 14 | 10–80 | Any time of day |
Fluvastatin | II | Indole | Lipophilic | Passive | 1.2 | 20–80 | Bedtime |
Lovastatin | I | Naphthalene | Lipophilic | Passive | 3 | 10–80 | Morning and evening |
Pitavastatin | II | Quinoline | Lipophilic | Passive | 12 | 1–4 | Any time of day |
Pravastatin | I | Naphthalene | Hydrophilic | Active | 1.8 | 10–80 | Bedtime |
Rosuvastatin | II | Pyrimidine | Hydrophilic | Active | 19 | 5–40 | Any time of day |
Simvastatin | I | Naphthalene | Lipophilic | Passive | 2 | 5–40 | Evening |
Statin | Cancer Type | Dose (mg/day) | Combination Agent | Trial Phase | Recruitment Status | Clinical Trial Number |
---|---|---|---|---|---|---|
Atorvastatin | Breast | 40 | Fulvestrant, Letrozole | Phase 2 | Recruiting | NCT02958852 |
80 | NT | Phase 3 | Recruiting | NCT04601116 | ||
80 | ACT/NCT | Phase 2; Phase 3 | Recruiting | NCT05103644 | ||
20–80 | NCT | Phase 2 | Recruiting | NCT03872388 | ||
Colorectal | 20 | Aspirin | Phase 1 | Recruiting | NCT04379999 | |
Not Specified | N/A | Phase 2 | Recruiting | NCT04767984 | ||
Head and Neck | 20 | ACT/NCT, ART/NRT | Phase 3 | Not Recruiting | NCT04915183 | |
Hepatocellular | 10 | N/A | Phase 4 | Recruiting | NCT03024684 | |
Pancreatic | 80 | Ezetimibe/Ezetrol, Evolocumab/Repatha, ACT | Phase 1 | Recruiting | NCT04862260 | |
Prostate | 80 | ADT | Phase 3 | Recruiting | NCT04026230 | |
80 | Acetylsalicylic acid | Phase 3 | Recruiting | NCT03819101 | ||
Not Specified | Pentoxifylline, Vitamin E, ART/NRT | Phase 2 | Recruiting | NCT03830164 | ||
Solid tumor, AML | 80 | N/A | Phase 1 | Recruiting | NCT03560882 | |
Pitavastatin | AML, CLL | 1–4 | Venetoclax | Phase 1 | Recruiting | NCT04512105 |
Breast | 2 | NCT | Phase 2; Phase 3 | Not Recruiting | NCT04705909 | |
40 | ART | Phase 3 | Recruiting | NCT04385433 | ||
40 | ART | Phase 2 | Recruiting | NCT04356209 | ||
AML | 1280 | ACT/NCT | Phase 2 | Not Recruiting | NCT00840177 | |
Rosuvastatin | Endometrial | 10 | Megestrol Acetate | Phase 2 | Recruiting | NCT04491643 |
Ovarian | Not Specified | Enoxaparin, Thromboprophylaxis | Phase 2 | Not Recruiting | NCT03532139 | |
Melanoma, Solid tumor | 10 | Bupropion, ACT/NCT | Phase 1 | Recruiting | NCT03864042 | |
Solid tumor | Not Specified | Sitravatinib, Nivolumab | Phase 1 | Recruiting | NCT04887194 | |
Simvastatin | Breast | 40 | ACT/NCT | Phase 2 | Not Recruiting | NCT02096588 |
20 | N/A | Phase 3 | Recruiting | NCT03971019 | ||
80 | HER2 Therapy | Phase 2 | Recruiting | NCT03324425 | ||
Not Specified | N/A | Phase 2 | Not Recruiting | NCT03454529 | ||
Liver | Not Specified | N/A | Phase 2 | Not Recruiting | NCT02968810 | |
Lung | 40 | AZD9291 | Phase 1 | Not Recruiting | NCT02197234 | |
Ovarian | 40 | ACT/NCT | Phase 1 | Recruiting | NCT04457089 | |
Lung | 20 | ACT/NCT | Phase 2 | Recruiting | NCT04698941 | |
40 | ACT/NCT | Phase 2 | Not Recruiting | NCT04985201 | ||
40 | ACT/NCT | Phase 2 | Not Recruiting | NCT01441349 |
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Share and Cite
Pereira, M.; Matuszewska, K.; Glogova, A.; Petrik, J. Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy. Cancers 2022, 14, 3500. https://doi.org/10.3390/cancers14143500
Pereira M, Matuszewska K, Glogova A, Petrik J. Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy. Cancers. 2022; 14(14):3500. https://doi.org/10.3390/cancers14143500
Chicago/Turabian StylePereira, Madison, Kathy Matuszewska, Alice Glogova, and Jim Petrik. 2022. "Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy" Cancers 14, no. 14: 3500. https://doi.org/10.3390/cancers14143500