Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lovastatin, a drug commonly used in the clinic to treat hypercholesterolemia, has previously been reported to exert antitumor effects in rodent tumor models and to strengthen the antitumor effects of immune response modifiers (tumor necrosis factor alpha and IFN-gamma) or chemotherapeutic drugs (cisplatin). In the present report, we show in three murine tumor cell lines (Colon-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) that lovastatin can also effectively potentiate the cytostatic/cytotoxic activity of doxorubicin. In three tumor models (Co-ion-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (15 mg/kg for 10 days) and doxorubicin (3 x 2.5 mg/kg; cumulative dose, 7.5 mg/kg) as compared with either agent acting alone. Lovastatin treatment also resulted in a significant reduction of troponin T release by cardiomyocytes in doxorubicin-treated mice. This observation is particularly interesting because lovastatin is known to reduce doxorubicin-induced cardiac injury.
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PMID:Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice. 1081 31

Lovastatin (Lov), bisphosphonates (BP) and metformin (Met) are widely used drugs, having in common that they interfere with the mevalonate pathway (MP). The MP generates isoprene moieties required for the function of regulatory GTPases controlling cell proliferation and survival. Here, we addressed the question whether MP inhibitors interfere with the anti-tumor efficacy of anticancer drugs. We comparatively analyzed the effect of equitoxic doses of Lov, BP and Met on cell viability, cell cycle progression, apoptosis and DNA damage response (DDR) of human osteo- and fibrosarcoma cells exposed to doxorubicin or cisplatin. We found that Lov, BP and Met modulated the anticancer drug sensitivity of sarcoma cells in an agent-, dose and time-dependent fashion. Mostly, the MP inhibitors increased the cytotoxicity of the anticancer drugs in an additive manner. MP modulators differed from each other regarding their impact on anticancer drug-induced DNA damage response as measured by the phosphorylation status of SAPK/JNK, Chk-1 and H2AX as well as p53 protein level. In this regard, lovastatin and metformin turned out as the most effective inhibitory drugs. The data show that MP inhibitors can affect the anti-tumor efficacy of anticancer drugs and impact the DDR of human sarcoma cells.
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PMID:Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells. 2135 74

Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. In mice, lovastatin mitigated acute doxorubicin-induced heart and liver damage as indicated by reduced mRNA levels of the pro-fibrotic cytokine connective tissue growth factor (CTGF) and pro-inflammatory cytokines, respectively. Lovastatin also protected from doxorubicin-provoked subacute cardiac damage as shown by lowered mRNA levels of CTGF and atrial natriuretic peptide. Increase in the serum concentration of troponin I and cardiac fibrosis following doxorubicin treatment were also reduced by lovastatin. Whereas protecting the heart from harmful doxorubicin effects, lovastatin augmented its anticancer efficacy in a mouse xenograft model with human sarcoma cells. These data show that statins lower the incidence of cardiac tissue injury after anthracycline treatment in a Rac1-dependent manner, without impairing the therapeutic efficacy.
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PMID:Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity. 2183 28