====== Lovastatin for brain tumor treatment ======

An emerging approach to targeting [[cancer stem cell]]s (CSCs) in [[brain tumor]]s is through repurposing the [[lipid]]-lowering medication, [[lovastatin]]. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that impacts the [[mevalonate pathway]]. The inhibition of intermediates in the [[mevalonate pathway]] affects signaling cascades and [[oncogene]]s associated with [[brain]] [[tumor stem cell]]s (BTSC). In a review, Amadasu et al. from the  [[University of South Florida]] showed the possible mechanisms where lovastatin can target BTSC for different varieties of [[malignant]] [[brain tumor]]s
((Amadasu E, Kang R, Usmani A, Borlongan CV. Effects of [[Lovastatin]] on Brain [[Cancer Cell]]s. Cell Transplant. 2022 Jan-Dec;31:9636897221102903. doi: 10.1177/09636897221102903. PMID: 35670207.)).
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Zhu et al. investigated the combinational effects of [[lovastatin]] and [[temozolomide]] on treating [[U87]] and [[U251]] Glioblastoma cell lines. Cytotoxicity was measured by MTT and colony formation assays; apoptosis was measured by flow cytometry; the cellular autophagic function was detected by the EGFP-mRFP-LC3 reporter and western blot assay. The results showed that lovastatin might enhance the cytotoxicity of TMZ, increase the TMZ-induced cellular apoptosis, and impair the autophagic flux in Glioblastoma cells. Lovastatin triggered autophagy initiation possibly by inhibiting the Akt/mTOR signaling pathway. Moreover, lovastatin might impair the autophagosome-lysosome fusion machinery by suppressing LAMP2 and dynein. These results suggested that lovastatin could enhance the chemotherapy efficacy of TMZ in treating Glioblastoma cells. The mechanism may be associated with impaired autophagic flux and thereby the enhancement of cellular apoptosis. Combining TMZ with lovastatin could be a promising strategy for Glioblastoma treatment
((Zhu Z, Zhang P, Li N, Kiang KMY, Cheng SY, Wong VK, Leung GK. Lovastatin Enhances Cytotoxicity of Temozolomide via Impairing Autophagic Flux in Glioblastoma Cells. Biomed Res Int. 2019 Sep 23;2019:2710693. doi: 10.1155/2019/2710693. PMID: 31662972; PMCID: PMC6778891.)).
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Human glioblastoma cells were found to be uniquely vulnerable to growth arrest by lovastatin, a competitive inhibitor of the enzyme regulating MVA synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The sodium salt of phenylacetic acid (NaPA), an inhibitor of MVA-pyrophosphate decarboxylase, the enzyme that controls MVA use, acted synergistically with lovastatin to suppress malignant growth. When used at pharmacologically attainable concentrations, the two compounds induced profound cytostasis and loss of malignant properties such as invasiveness and expression of the transforming growth factor-beta 2 gene, coding for a potent immunosuppressive cytokine. Supplementation with exogenous ubiquinone, an end product of the MVA pathway, failed to rescue the cells, suggesting that decreased synthesis of intermediary products is responsible for the antitumor effects observed. In addition to blocking the MVA pathway, lovastatin alone and in combination with NaPA increased the expression of the peroxisome proliferator-activated receptor, a transcription factor implicated in the control of lipid metabolism, cell growth, and differentiation. Our results indicate that targeting lipid metabolism with lovastatin, used alone or in combination with the aromatic fatty acid NaPA, may offer a novel approach to the treatment of malignant gliomas
((Prasanna P, Thibault A, Liu L, Samid D. Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin and sodium phenylacetate against human glioma cells. J Neurochem. 1996 Feb;66(2):710-6. doi: 10.1046/j.1471-4159.1996.66020710.x. PMID: 8592143.)).