Novel therapy for malignant pleural mesothelioma based on anti-energetic effect: an experimental study using 3-Bromopyruvate on nude mice.

BACKGROUND Most cancer cells exhibit increased anaerobic glycolysis and use this metabolic pathway for the generation of ATP as a main source of energy. This impaired metabolism of glucose, leading to the secretion of lactic acid even in the presence of oxygen, is named the Warburg effect. Because cancer cells are partly or mainly dependent on such a pathway to generate ATP, inhibition of glycolysis may slow down the proliferation or kill cells. MATERIALS AND METHODS The effect of 3-Bromopyruvate (3-BrPA) alone or associated to cisplatin on nude mice presenting intraperitoneal carcinomatosis developed after intraperitoneal injection of human mesothelioma cells (MSTO-211H) was investigated. RESULTS 3-BrPA significantly prolonged survival of animals. Combined with cisplatin, it demonstrated significant benefit on survival whereas cisplatin alone had no or a mild effect. CONCLUSION 3-BrPA may thus constitute an interesting novel anticancer drug that could be tested in humans.

[1]  J. Neuzil,et al.  A vitamin E analogue suppresses malignant mesothelioma in a preclinical model: A future drug against a fatal neoplastic disease? , 2004, International journal of cancer.

[2]  J. Ribak,et al.  Survival of asbestos insulation workers with mesothelioma. , 1992, British journal of industrial medicine.

[3]  G. Giaccone,et al.  Apoptosis: target of cancer therapy. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  L. Altucci,et al.  Piroxicam and Cisplatin in a Mouse Model of Peritoneal Mesothelioma , 2006, Clinical Cancer Research.

[5]  Lundin Lg,et al.  Iron-catalyzed reactions may be responsible for the biochemical and biological effects of asbestos. , 1991 .

[6]  G. Santoni,et al.  Characterization of human malignant mesothelioma cell lines orthotopically implanted in the pleural cavity of immunodeficient mice for their ability to grow and form metastasis , 2006, BMC Cancer.

[7]  Martin G Pomper,et al.  Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. , 2004, Biochemical and biophysical research communications.

[8]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[9]  W. Lieberthal,et al.  Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. , 1998, American journal of physiology. Renal physiology.

[10]  S. R. Datta,et al.  BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis , 2003, Nature.

[11]  P. Pedersen,et al.  Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. , 2002, Cancer research.

[12]  A. Aust,et al.  Iron-catalyzed reactions may be responsible for the biochemical and biological effects of asbestos. , 1991, BioFactors.

[13]  P. Nicotera,et al.  Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis , 1997, The Journal of experimental medicine.

[14]  E. Morselli,et al.  Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death , 2008, Oncogene.

[15]  P. Pedersen,et al.  Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. , 2001, Cancer letters.

[16]  Laurent Schwartz,et al.  Effect of 2-deoxy-D-glucose on various malignant cell lines in vitro. , 2006, Anticancer research.

[17]  R. Brown,et al.  Cisplatin- and paclitaxel-induced apoptosis of ovarian carcinoma cells and the relationship between bax and bak up-regulation and the functional status of p53. , 1998, Molecular pharmacology.

[18]  Peng Huang,et al.  Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. , 2005, Cancer research.

[19]  F Levi,et al.  The European mesothelioma epidemic , 1999, British Journal of Cancer.