Ritonavir has anti-neoplastic effects independent of HIV inhibition

In vitro and in vivo data show that the HIV protease inhibitor ritonavir decreases production of factors that contribute to tumor neovascularization and the development of Kaposi sarcoma (KS).

“We found that ritonavir has significant side effects on immune cell activation,” Dr Frank F Weichold from Morgan State University, Baltimore, told Reuters Health. “It is, in a way, an antiinflammatory [agent]. So ritonavir is not only an antiviral, but also an immune [system] modulator,” he explained. Dr Weichold and colleagues treated KS cells, from a KS cell line, and endothelial cells, from human umbilical veins, with different concentrations of ritonavir over 24 hours.

Compared with untreated cultures, a high concentration of ritonavir (50 µmol/L) reduced the number of viable primary human umbilical vein endothelial cells by approximately 25%, the researchers noted. The researchers also treated human umbilical vein endothelial cells with ritonavir and used ELISA to measure cytokines levels, according to the report in the May 15th issue of Blood. After 48 hours, there were decreases in the levels of interleukin-8, and after 24 hours, there were decreases in tumour necrosis factor-alpha and in vascular endothelial growth factor. These cytokines may all contribute to the development of KS and the perpetuation of KS lesions, Dr Weichold’s team comments.

Ritonavir also inhibited leukocyte adhesion to endothelial cells. This inhibition was dose-dependent, “with less than 60% of adherent cells remaining at concentrations higher than 30 µmol/L.” The research team also found that ritonavir inhibited transcriptional activation of nuclear factor kappa-B, induced by the KS-promoting factor tumour necrosis factor-alpha, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74.

“KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3 to 15 µM),” they add. In a KS-tumor xenotransplantation mouse model, Dr Weichold’s team also found that ritonavir at 30 mg/kg per day for 15 days slowed the growth of KS-derived cells and significantly inhibited tumour development.

These effects have implications for the use of ritonavir as an antiinflammatory. Also, ritonavir inhibits cellular proteases that might be useful in treating cancer, Dr Weichold said. “We believe that ritonavir might be beneficial in treating solid tumours by inhibiting neovascularization,” he continued. And ritonavir might make leukemia cells more susceptible to other anticancer drugs.