HIV Protease Inhibitors Block Akt Signaling and Radiosensitize Tumor Cells Both In vitro and In vivo

Abstract

In tumor cells with mutations in epidermal growth factor receptor (SQ20B

Immunomodulation in female B6C3F1mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage

“…There is increasing incidence of non-AIDS defining neoplasms in HIV-1 + individuals in the post HAART-era, but the pathogenicity has not yet been determined (Knysz et al, 2006). Our data do not suggest any associations between SQV exposure and an increased tumor incidence after HAART; this is further corroborated by the reports that SQV is a potent anti-angiogenic molecule (Sgadari et al, 2003) and a radiation sensitizer for non-HIV-associated cancers (Pajonk et al, 2002;Gupta et al, 2005).…”

The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

“…HIV-PIs inhibit the growth of numerous types of tumor cell lines, including multiple myeloma, SW872 liposarcoma, T24 bladder carcinoma, A549 lung carcinoma, U373 glioblastoma, Jurkat leukemia cells, DU-145 and PC-3 prostate cancer cells, NB4 and HL-60 human myelocytic leukemia cells, and Kaposi's sarcoma (6,7,9,12,14). These drugs are capable of decreasing the incidence of Kaposi's sarcoma and promoting its regression, and of amplifying the therapeutic efficacy of radiotherapy and chemotherapy of head, neck, bladder, and prostate cancers (7,8,10,11,13,14). However, long-term administration of HIV-PIs results in serious adverse side effects, including hyperbilirubinemia, hyperlipidemia or hypolipidemia, insulin resistance, and diabetes, among others (2).…”

“…Although their mechanism of action against cancer cells is not completely understood, the potential targets of these drugs may include Akt, extracellular signal-regulated kinase, nuclear factor κB, signal transducers and activators of transcription 3, matrix metalloproteinase, basic fibroblast growth factor, and vascular endothelial growth factor (7,(10)(11)(12)(13). In addition, these drugs have been shown to sensitize tumor cells to radiation, enhance the anticancer effects of other cytostatic drugs, and to inhibit the growth and invasion of angiogenic tumor cells in nude mice (10,11,14).…”

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

“…Recent reports show that SQV inhibits vascular remodeling in pulmonary artery hypertension and inflammation in nephritis (32)(33)(34)(35)(36)(37). Metalloproteinases 2 and 20S and 26S proteasomes are proposed protease targets in mammalian tissues (32)(33)(34)(35)(36)(37).…”