Kaposi's Sarcoma (KS) is a type of tumor caused by the human herpesvirus 8 that often develops in AIDS patients with weakened immune systems. In the case of AIDS-related KS, highly active antiretroviral therapy (HAART) can induce significant regression of the disease; however, HAART is not always effective and second-line therapies for KS include chemotherapeutic intervention. Anthracyclines such as doxorubicin are frequently used in the treatment of AIDS-related KS but resistance to these agents does arise. Taxanes such as paclitaxel and docetaxel have successfully been used to treat doxorubicin-resistant KS. However, no studies have examined the potential resistance mechanisms to taxanes in KS. As HAART is often administered concomitantly with chemotherapy when treating AIDS-related KS, it is important to examine the effects of recently-approved antivirals on potential resistance mechanisms to chemotherapy used to treat KS. Our interest in resistance mechanisms in Kaposi's sarcoma comes from our previous work with the ATP-dependent transporter P-glycoprotein (P-gp). We previously demonstrated that P-gp can hamper HIV virus production and decrease infectivity in cells that overexpress the transporter. Additionally, a number of HIV protease inhibitors have been shown to be substrates of P-gp. In one cell line model of Kaposi's sarcoma, we found that anthracycline treatment leads to increased P-gp expression and that HIV protease inhibitors can further augment this expression. However, the cell line used for this study was recently shown to be mischaracterized, thus requiring a reevaluation of these results. Our current work focuses on the L1T2 cell line that has been shown to recapitulate clinical features of Kaposi's sarcoma in mouse models. We have characterized the drug resistance pattern of this cell line and are isolating resistant sublines of the L1T2 line to identify potential mechanisms of resistance using a Taq-man low-density array microfluidic chip to detect mRNA expression of 380 drug resistance-related genes comprising genes involved in drug efflux, DNA repair mechanisms, apoptosis and metabolizing enzymes. Additionally, these results will allow us to characterize the role that HIV protease inhibitors play in inducing or preventing resistance to chemotherapy. Ultimately we hope that identification of novel mechanisms of resistance in Kaposi's sarcoma will lead to improved therapies.
