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.
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 synergy. In contrast, significant downregulation of cyclooxygenase-2 (COX-2) expression and activity was observed in the cells exposed to SN-38 in combination with MSC compared to SN-38 alone. Moreover, the inhibition of PGE(2) production was also observed in the cells treated with the combination as compared with SN-38 alone. Analysis of tumor tissues at 24 h after treatment with synergistic modality of irinotecan and MSC revealed significant downregulation of COX-2, inducible nitric oxide synthase (iNOS) and hypoxia-induced factor-1alpha expression (HIF 1alpha). Moreover, decreased microvessel density was observed after irinotecan treatment with the addition of MSC. These results suggest that observed therapeutic synergy correlates with the inhibition of neoangiogenesis through the downregulation of COX-2, iNOS and HIF-1alpha expression.
Yin
M-B
MB
Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Li
Z-R
ZR
Tóth
K
K
Cao
S
S
Durrani
F A
FA
Hapke
G
G
Bhattacharya
A
A
Azrak
R G
RG
Frank
C
C
Rustum
Y M
YM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000008:administration & dosage; D017279:Selenocysteine / Q000031:analogs & derivatives; D014183:Transplantation, Heterologous
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016566:Organoselenium Compounds; D017279:Selenocysteine; D000077146:Irinotecan; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D003545:Cysteine; C002979:selenomethylselenocysteine; D002166:Camptothecin