The Potential Role of Delta(9)-Tetrahydrocannabinol in the Pathogenesis of Kaposi’s Sarcoma.

Kaposi’s sarcoma (KS) is a frequent neoplastic manifestation of immuno-compromised conditions such as AIDS and organ transplantation. The etiologic agent of the tumor is the KS-associated herpesvirus (KSHV), also known as human herpesvirus 8. Other factors, including HIV-1 Tat protein, may also contribute to the development and progression of KS in people with AIDS. Marijuana is the most commonly used illicit drug in the United States. In addition, its major active component, THC (Tetrahydrocannabinol), is prescribed for medicinal use. This includes treatment of HIV-related cachexia as well as pain and wasting in other immuno-compromised patients. However, relatively limited knowledge exists about the effects of cannabinoids on KS growth and spread. To investigate how cannabinoids may affect KS from the initiation of KSHV infection to proliferation of KS spindle cells, we first assessed whether KS spindle cells expressed cannabinoid receptors. The CB1 and CB2 receptors were detected on KS cells by flow cytometry. These receptors were found to be functional based on calcium flux upon ligand stimulation. We then sought to determine whether cannabinoids modulated viral entry. KSHV infection was quantitated in primary microvascular endothelial cells in the presence of a dose range of THC. We observed that low concentrations of Δ⁹-THC (less than 1 ng/ml) increased KSHV infection by about 30%. Higher concentrations of Δ⁹-THC induced significant cell death following KSHV exposure. Blocking of the CB1 and CB2 receptors had no effect on THC-modulated KSHV infection. We then studied the functional and biochemical changes in KS spindle cells after exposure to cannabinoids. We observed a dose-dependent inhibition of growth in these spindle cells in the presence of Δ⁹-THC. To elucidate the molecular mechanism of growth inhibition, we assayed signaling molecules involved in cell survival and proliferation. We found that Δ⁹-THC activated ERK1/2 MAP kinase and Akt, as well as VEGFR-2 and EGFR in KS spindle cells. High concentrations of Δ⁹-THC significantly inhibited VEGF-C and VEGF-D secretion but not VEGF-A production. Since KS is a vascular neoplasm and blockade of the CB1 and CB2 receptors did not antagonize the effects of Δ⁹-THC in KS, we investigated the activity of abn-cbd [(−)-4-(3-3, 4-trans-p-menthadien-[1, 8]-yl)-olivetol], a novel selective cannabinoid-like agonist specific for endothelium. Similar inhibitory effects in response to abn-cbd were observed in the KS spindle cells. These inhibitory effects were reversed by ARA-S (N-Arachidonoyl Serine) and O-1918 [(−)-4-(3-3, 4-trans-p-menthadien-(1, 8)-yl)-orcinol], specific antagonists of abn-cbd. These antagonists also reversed the reduction in VEGF-C and VEGF-D production. Taken together, our study indicates a biphasic effect of Δ⁹-THC, in that the cannabinoid may enhance KSHV infection at low concentrations, but inhibit KS spindle cell growth at higher concentrations. This modulation of KS cell function may involve a third putative receptor other than CB1 and CB2. Further knowledge regarding cannabinoid modulation of KS biology should allow for a greater understanding of the appropriate use of marijuana and its active constituents in immuno-suppressed hosts at risk for KS.