“Treatment of cancer patients with lipid metabolic inhibitors like ranolazine could potentially re-activate the immune cells to restore and enhance cellular-mediated antitumor immunity and tumor regression.”
Targeting Fat Oxidation in Mouse Prostate Cancer Decreases Tumor Growth and Stimulates Anti-Cancer Immunity
by Amanda Guth 1, Emily Monk 2ORCID, Rajesh Agarwal 3, Bryan C. Bergman 4, Karin A. Zemski-Berry 4, Angela Minic 5ORCID, Kimberly Jordan 5 and Isabel R. Schlaepfer 2,*ORCID 1
Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, CO 80523, USA 2
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 3
School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 4
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 5
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Submission received: 19 November 2020 / Revised: 12 December 2020 / Accepted: 15 December 2020 / Published: 18 December 2020
Abstract
Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression.
Here’s another paper with some epidemiological human evidence.
“A key question was whether the life expectancy of cancer patients taking ranolazine for non-cancer indications (e.g., angina pectoris) would differ from that of patients not using ranolazine. Data from breast, colon and prostate cancers over a 10-year period were pooled. Of these ca. 54,000 patients, a subgroup of 165 individuals were found to have taken ranolazine at various stages of their cancer. Prescriptions had started either before diagnosis and extended afterwards or started on average 4 years post-diagnosis. This group was compared with patients who did not take ranolazine. For the study group taking ranolazine (in the concentration range used for treating angina pectoris), the hazard ratio was ca. 0.41 (i.e., risk of dying from cancer was reduced by 59%) and this effect was a highly significant (p < 0.001). For those patients who started taking ranolazine after diagnosis, the hazard ratio was slightly higher (0.54) but the beneficial effect was still significant (p < 0.01).”
Ranolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels
Mustafa B. A. Djamgoz
British Journal of Cancer (2024)Cite this article
Abstract
Background
Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (INaP) which can be blocked selectively by ranolazine.
Methods
Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients.
Results
In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by co-administration with other drugs.
Conclusions
Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic drug offering many potential advantages over current systemic treatment modalities.
This looks like another great alternative therapy. The problem with all these alternative therapies is trying to get a doctor to prescribe these drugs. I am constantly suggesting possible drugs that could have a benefit and the doctors do not respond. All the doctors that I have been working with will not prescribe these drugs. The question is how do you access these drugs?
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