In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Authors: Ulivi, P.; Arienti, C.; Zoli, W.; Scarsella, M.; Carloni, S.; Fabbri, F.; Tesei, A.; Chiadini, E.; Orlandi, A.; Passeri, D.; Zupi, G.; Milandri, C.; Silvestrini, R.; Amadori, D.; Leonetti, C.

Source: Current Cancer Drug Targets, Volume 10, Number 6, September 2010 , pp. 600-610(11)

Publisher: Bentham Science Publishers

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Abstract:

The response of pancreatic cancer to treatments remains unsatisfactory, highlighting the need for more effective therapeutic regimens. Sorafenib, an orally available multikinase inhibitor, is active against different tumors, including pancreatic cancer. We studied the antitumor efficacy of sorafenib in combination with different antitumor drugs currently used in clinical practice in in vitro and in vivo experimental models of human pancreatic cancer. The cytotoxic effect of sorafenib and conventional antitumor drug combinations was evaluated in vitro in human pancreatic cancer cell lines and the efficacy of the most active combination was tested on tumor-bearing mice. Flow cytometric, Western blot and immunohistochemistry analyses were performed to investigate the mechanisms involved in the activity of single drugs and in their interaction when used in combination. Sorafenib showed a strong sequence-dependent synergistic interaction in vitro with docetaxel, which was highly dependent on the drug sequence employed. In vivo, human pancreatic cancer-xenografted mice treated with docetaxel followed by sorafenib reduced and delayed tumor growth, with complete tumor regression observed in half of the mice. This marked antitumor effect resulted in an overall increase in mouse survival of about 70% and in a complete cure in 3 of the 8 treated mice. The strong activity was also accompanied by marked apoptosis induction, inhibition of tumor angiogenesis and downregulation of ERK signalling. Our results show that the docetaxel and sorafenib combination exerts high therapeutic efficacy in experimental models of human pancreatic cancer, indicating a promising antitumor strategy for clinical use.





Keywords: Angiogenesis; apoptosis; combination therapy; pancreatic cancer cell lines; xenografts

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/156800910791859489

Publication date: September 1, 2010

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  • Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
    Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
    As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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