HIV-1 Protease Inhibitor, Ritonavir

Abstract

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10 ؊5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor B (NFB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin

“…This in turn can explain a lack of correlation between GLUT4 expression and sensitivity to ritonavir among the samples tested. Additional mechanisms for ritonavir mediated cytotoxicity that have been investigated in other cancer cell contexts include inhibition of NFκB, inhibition of Akt, enhancement of protein ubiquitination, HDAC suppression and histone deacetylation 32–34 . These additional targets of ritonavir could explain the observed cytotoxicity in the samples tested and lack of correlation with GLUT4 expression.…”

Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells

“…Membrane protein inhibitors can enhance docetaxel-induced apoptosis of androgen-independent PC cells. Those inhibitors, including IL-6 [6], ritonavir [7], and PD98059 [8], can prevent the progress of cancer cells and prolong the sensitivity to chemotherapy by blocking some pathways in malignant transformation and drug resistance, such as RAF/MEK/ERK and PI3K/PTEN/AKT [8,9,10]. Proteomics has been widely used in cancer research, including the study and characterization of protein production and the definition of protein function, to allow improved monitoring of therapy response and disease relapse, as well as aid in the engineering of new drugs and strategies to circumvent resistance mechanisms while avoiding the adverse effects of traditional chemotherapy.…”

Subverting ER-Stress towards Apoptosis by Nelfinavir and Curcumin Coexposure Augments Docetaxel Efficacy in Castration Resistant Prostate Cancer Cells

“…Its sensitizing effects have been linked to the induction of ER-stress and the inhibition of AKT pathway [28]. Indeed, ritonavir, another HPI with similar mechanism of action, was also shown to enhance the anticancer effects of DTX in a highly aggressive PCa cell line, DU-145 [29]. However, the sensitizing effects of NFR are only exhibited at concentrations of ≥10 µM, which is higher than its safe and physiologically-achievable levels, i.e.…”