Barillari et al. have reported interesting data in their recent article. Interestingly, recent data suggest that ritonavir may also exert significant antineoplastic effects in other systemic malignancies.
For example, attenuation of tumor growth is seen in mammary malignancies. Cyclin D1 levels are markedly attenuated. Estrogen receptor α levels are also decreased at the same time. The attenuation of phosphorylated Rb levels accompanies the above changes . As a result, there is increased G1 phase arrest within the tumor cells. Akt activity also suffers and is decreased markedly. Similar effects are seen in ovarian malignancies. Increased G1/growth 1 phase arrest is seen in the ovarian cancer cells. It mediates this effect by attenuating Rb phosphorylation. Akt phosphorylation is also downregulated at the same time . These effects are dose-dependent.
A similar benefit has been noted in pulmonary malignancies. It mediates this role by markedly attenuating survivin levels within the tumor cells. Simultaneous poly-ADP-ribose polymerase 1 cleavage enhancement is seen. ‘Signal transducer and activator of transcription protein 3’ activity is also decreased . As a result, it causes G0/G1 phase arrest. Cyclin D1 expression is decreased at the same time. In addition, ritonavir exhibits synergistic activity when administered along with chemotherapeutic agents such as cisplatin and gemcitabine. Simultaneously, c-Src phosphorylation is inhibited. A similar benefit has been noted in renal carcinomas. For example, significant attenuation of tumor growth has been seen when ritonavir is administered with chemotherapeutic agents such as bortezomib. The combination has a synergistic effect in accentuating protein ubiquitination and also decreases histone deacytelase expression markedly . A similar benefit is noted in renal carcinomas when ritonavir is administered along with suberoylanilide hydroxamic acid. This combination exerts its effects by augmenting histone acetylation . Simultaneous accentuation of dephosporylation of Rb is also seen.
The above examples illustrate the significant antineoplastic effects of ritonavir and the need for further studies in this regard.
Conflicts of interest
There are no conflicts of interest.
1. Barillari G, Iovane A, Bacigalupo I, Palladino C, Bellino S, Leone P, et al. Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity
2. Srirangam A, Milani M, Mitra R, Guo Z, Rodriquez M, Kathuria H, et al. The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin
. J Thorac Oncol
3. Kumar S, Bryant CS, Chamala S, Qazi A, Seward S, Pal J, et al. Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells
. Mol Cancer
4. Sato A, Asano T, Ito K, Asano T. Ritonavir interacts with bortezomib to enhance protein ubiquitination and histone acetylation synergistically in renal cancer cells
5. Sato A, Asano T, Horiguchi A, Ito K, Sumitomo M, Asano T. Combination of suberoylanilide hydroxamic acid and ritonavir is effective against renal cancer cells