In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells.

BACKGROUND: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. METHODS: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. RESULTS: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. CONCLUSIONS: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.

Utility of a Mycobacterium tuberculosis GC-rich repetitive sequence in the diagnosis of tuberculous pleural effusion by PCR.

A GC-rich repetitive sequence (GCRS) of Mycobacterium tuberculosis was identified in our laboratory which displayed a high homology with GC-rich sequences of M. tuberculosis and M. bovis. A PCR assay based on the amplification of the proximal 150 bp of GCRS and its detection by non-radioactive hybridization was developed. The accuracy of the GCRS-based PCR assay was evaluated in a clinical setting for the detection of mycobacterial DNA in pleural fluids for the diagnosis of tuberculosis (TB) using clinical criteria and pleural biopsy histology as gold standard. In a blind study, a total of 67 pleural fluid samples (38 tuberculous and 29 nontuberculous) were analysed by PCR and the results were compared with pleural biopsy, Ziehl-Neelsen staining and culture. Mycobacteria could not be detected by either smear or culture techniques in any of the pleural fluids samples. Out of 38 tuberculous pleural effusions, 24 were positive by PCR (63.2% sensitivity). When PCR results were compared with pleural biopsy histology, an increased sensitivity of 73.3% was obtained. Out of the 29 nontuberculous pleural effusions, 2 false positive results were obtained accounting for an overall specificity of 93.1%. The GCRS-based PCR assay thus has a definite role in the diagnosis of tuberculous pleural effusion in contrast to smear and/or culture techniques.