Abstract
Malignant pleural mesothelioma (MPM) is a poor prognosis disease lacking adequate therapy. We have previously shown that ascorbic acid administration is toxic to MPM cells. Here we evaluated a new combined therapy consisting of ascorbate/epigallocatechin-3-gallate/gemcitabine mixture (called AND, for Active Nutrients/Drug). In vitro effects of AND therapy on various MPM cell lines revealed a synergistic cytotoxic mechanism. In vivo experiments on a xenograft mouse model for MPM, obtained by REN cells injection in immunocompromised mice, showed that AND strongly reduced the size of primary tumor as well as the number and size of metastases, and prevented abdominal hemorrhage. Kaplan Meier curves and the log-rank test indicated a marked increase in the survival of AND-treated animals. Histochemical analysis of dissected tumors showed that AND induced a shift from cell proliferation to apoptosis in cancer cells. Lysates of tumors from AND-treated mice, analyzed with an antibody array, revealed decreased TIMP-1 and -2 expressions and no effects on angiogenesis regulating factors. Multiplex analysis for signaling protein phosphorylation exhibited inactivation of cell proliferation pathways. The complex of data showed that the AND treatment is synergistic in vitro on MPM cells, and blocks in vivo tumor progression and metastasization in REN-based xenografts. Hence, the AND combination is proposed as a new treatment for MPM.
Highlights
Malignant pleural mesothelioma (MPM) is a lethal cancer arising from pleura mesothelial cells, showing a close association with previous exposure to asbestos
Active Nutrients/Drug (AND) therapy has a synergistic action in decreasing the viability of MPM cell lines In a previous study based on the Chou and Talalay’s combination index (CI) method [27], we had shown that ascorbate/gemcitabine and ascorbate/EGCG combinations have synergistic cytotoxic activity on REN cells, an established cell model of MPM [16]
Here we show that a triple combined treatment based on EGCG, ascorbate and gemcitabine (AND therapy) reduces mesothelioma growth and metastasization
Summary
Malignant pleural mesothelioma (MPM) is a lethal cancer arising from pleura mesothelial cells, showing a close association with previous exposure to asbestos. This tumor is characterized by long latency period (20–30 years) and slow growth which cause late diagnosis, poor prognosis, and limited effective therapies. Decisions of carrying out surgery, radiotherapy, chemotherapy or multimodal procedures are taken on a case-bycase basis, and frequently a palliative treatment is the only choice available [4]. Radiotherapy is mainly used as adjuvant therapy following surgery or for symptom relief [6]
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