Paclitaxel Induces Apoptosis in AIDS-Related Kaposi's Sarcoma Cells

Jie Cai,Guofu Fang,David R Hinton,Rizwan Masood,Tong Zheng,Caryn Nae Kim,D Lynne Smith,Parkash S Gill,Kapil Bhalla

doi:10.1155/s1357714x00000074

Abstract

Paclitaxel is a microtubule stabilizing drug that causes dividing cells to arrest and then undergo apoptosis. It also has antiangiogenic activity because it alters cytoskeletal structure, affecting migration and invasion. Paclitaxel is an effective treatment for AIDS-related Kaposi’s sarcoma (KS). KS is a tumor in which there is marked proliferation of endothelial cells in addition to the tumor cells, which themselves share many markers with activated (proliferating) endothelial cells.We sought to determine the mechanism by which paclitaxel exerts its anti-KS tumor effects. In vitro, KS cells are very sensitive to paclitaxel, with half-maximal growth inhibition observed at 0.8 nM. Inhibition of migration of KS cells was also observed at nanomolar concentrations of the drug. Paclitaxel induced cell cycle arrest with an accumulation of cells in sub-G1.This was accompanied in vitro by various events typical of apoptosis: phosphorylation of two anti-apoptotic proteins Bcl-2 and Bcl-xL , release of cytochrome c into the cytoplasm, cleavage and activation of caspase-3. In vitro results were borne out by studies of KS tumor xenografts in nude mice. Paclitaxel (10 mg/kg) inhibited tumor growth by 75% over 21 days. Histological examination of the tumors revealed a decrease in proliferative index, a decrease in the number of mitotic figures and an increase in apoptotic cells compared to tumors from untreated mice.

Highlights

Kaposi’s sarcoma is the most common tumor in patients with human immunode® ciency virus type 1 (HIV-1) infection.[1]
The immortalized Kaposi’s sarcoma (KS) cell lines KS Y-130 and KS-SLK31 were grown in wells coated with 1.5% gelatin in KS medium consisting of RPMI-1640 (Life Technologies, Gaithersburg, MD), 100 U/ml penicillin, 100 m g/ml streptomycin, 2 mM glutamine, 1% essential and non-essential amino acids, 10% fetal bovine serum (FBS: Life Technologies), and 1% Nutridoma-HU (Boehringer Mannheim, Indianapolis, IN)
Paclitaxel has proven effective in the treatment of a variety of cancers13± 15 including Phase II trials in Kaposi’s sarcoma.[16,39]

Summary

Introduction

Kaposi’s sarcoma is the most common tumor in patients with human immunode® ciency virus type 1 (HIV-1) infection.[1] Clinically, KS manifests most commonly on the skin and mucus membranes as multicentric lesions, with subsequent spread to visceral organs.[1] KS-related mortality is secondary to visceral organ disease. With the results of two groups that show clonality in KS lesions this debate appears to be resolving in favor of the neoplastic nature of the disease.[2,3]. Molecular epidemiology studies have shown that most KS tumors contain viral genome, suggesting an etiological link to this virus.[4] Seroepidemiology studies show that KS patients have a very high prevalence of KSHV/HHV8 antibodies (90%) which is elevated above the non-KS population (5± 20% in the USA). In countries with HIV but no documented KS, KSHV seroprevalence is very low (2± 4%).[5]

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Conclusion