Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced angiogenesis

Oncogene
M-B YinYoucef M Rustum

Abstract

Until recently, the use of Se-methylselenocysteine (MSC) as selective modulator of the antitumor activity and selectivity of anticancer drugs including irinotecan, a topoisomerase I poison, had not been evaluated. Therapeutic synergy between MSC and irinotecan was demonstrated by our laboratory in mice bearing human squamous cell carcinoma of the head and neck tumors. In FaDu xenografts, a poorly differentiated tumor-expressing mutant p53, the cure rate was increased from 30% with irinotecan alone to 100% with the combination of irinotecan and MSC. Cellular exposure to cytotoxic concentration of SN-38, the active metabolite of irinotecan (0.1 microM) alone and in combination with noncytotoxic concentration of MSC (10 microM) did not result in additional enhancement of chk2 phosphorylation and downregulation of specific DNA replication-associated proteins, cdc6, MCM2, cdc25A, nor increase in PARP cleavage, caspase activation and the 30-300 kb DNA fragmentation induced by SN-38 treatment. MSC did not alter significantly markers associated with apoptosis, nor potentiate irinotecan-induced apoptosis. These results indicate that apoptosis is unlikely to be one of the main mechanism associated with the observed in vivo therapeutic sy...Continue Reading

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Citations

Jan 13, 2010·Cancer Chemotherapy and Pharmacology·Sreenivasulu ChintalaYoucef M Rustum
Feb 24, 2009·The Journal of Pharmacology and Experimental Therapeutics·Dhaval K ShahJoseph P Balthasar
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Jun 11, 2011·Clinical and Experimental Medicine·Tian-bao WangWen-guang Dong
Jun 14, 2019·Journal of Cellular Biochemistry·Bagher FarhoodAmirhossein Ahmadi
Jul 3, 2021·International Journal of Molecular Sciences·Elena G Varlamova, Egor A Turovsky

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