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Abstract
The HIV protease inhibitors nelfinavir and saquinavir induce epithelial apoptosis in normal and malignant human colorectal mucosa and cancer cell lines
L. Lenzner1, H. Bode1, O.H. Krämer2, C. Loddenkemper3, A.J. Kroesen4, M. Zeitz1, R. Ullrich1
Background: Diarrhea is a frequent adverse effect of antiretroviral therapy in HIV infection. In HT-29/B6 colon cancer cell monolayers the HIV protease inhibitors (PIs) saquinavir (SQV) and nelfinavir (NFV) damage epithelial barrier function by apoptosis induction.
Methods: The intestinal epithelial cell lines HT-29/B6, T84, LS174T and Caco-2 were incubated with SQV and NFV and apoptotic cells were quantified by flow cytometry after propidium iodide staining. Tissue samples from resected colon carcinomas and normal adjacent mucosa were incubated for 24h with SQV and NFV and epithelial apoptosis was examined by histology and quantified by PARP western blots. PI concentrations used were those expected in the intestine after oral uptake, camptothecin (CPT) was used as positive control.
Results: In the cell lines examined 30-90 mM SQV and 35-140 mM NFV increased apoptotic rates in a dose-dependent manner by factor 3-22, which was comparable to the effect of CPT (table). NFV- and SQV-induced apoptosis was detectable after 12h and 18h, resp., and reached a maximum at 24h. Coincubation with low concentrations of CPT with SQV or NFV revealed more than additive effects on apoptosis induction. PARP cleavage in normal mucosa and in colorectal cancer tissue was increased by SQV, NFV, and CPT; histology revealed an increase of apoptotic epithelial cells.
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Conclusions: SQV and NFV induce apoptosis in colon cancer cell lines, in colon tumors, and in normal mucosa. In vivo, epithelial apoptosis may lead to barrier disruption which could cause leak-flux diarrhea. The apoptotic effects of PIs might be useful in antineoplastic therapy.
Supported by grants from BMBF (Competence Network HIV/AIDS, FKZ 01 KI 0211), Hoffman-La Roche AG, and Joachim-Kuhlmann-Stiftung.
AIDS 2006 - XVI International AIDS Conference
Abstract no.
CDB0695
Suggested Citation
"L.Lenzner, et al.
The HIV protease inhibitors nelfinavir and saquinavir induce epithelial apoptosis in normal and malignant human colorectal mucosa and cancer cell lines.
:
AIDS 2006 - XVI International AIDS Conference:
Abstract no.
CDB0695"
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