Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells Export

@article{citeulike:4389414, abstract = {Background: Ovarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy). Results: Here we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell line MDH 2774 in a dose dependent manner. After two day treatment, we observed cell death of 59\% in MDH 2774 cell line with 25 M (LD50). Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of pRB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir. Conclusions: Our results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside.}, author = {Kumar, Sanjeev and Bryant, Christopher S. and Chamala, Sreedhar and Qazi, Aamer and Seward, Shelly and Pal, Jagannath and Steffes, Christopher P. and Weaver, Donald W. and Morris, Robert and Malone, John M. and Shammas, Masood A. and Prasad, Madhu and Batchu, Ramesh B.}, citeulike-article-id = {4389414}, citeulike-linkout-0 = {http://dx.doi.org/10.1186/1476-4598-8-26}, day = {22}, doi = {10.1186/1476-4598-8-26}, issn = {1476-4598}, journal = {Molecular Cancer}, keywords = {immunomodulation, ovarian-cancer, pharmacotherapy, survival}, month = {April}, number = {1}, pages = {26+}, posted-at = {2009-10-26 15:13:07}, priority = {2}, title = {Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells}, url = {http://dx.doi.org/10.1186/1476-4598-8-26}, volume = {8}, year = {2009} }

TY - JOUR ID - citeulike:4389414 L3 - citeulike-article-id:4389414 N2 - Background: Ovarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy). Results: Here we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell line MDH 2774 in a dose dependent manner. After two day treatment, we observed cell death of 59% in MDH 2774 cell line with 25 M (LD50). Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of pRB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir. Conclusions: Our results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside. IS - 1 JF - Molecular Cancer SN - 1476-4598 TI - Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells VL - 8 SP - 26 KW - immunomodulation KW - ovarian-cancer KW - pharmacotherapy KW - survival AU - Kumar, Sanjeev AU - Bryant, Christopher AU - Chamala, Sreedhar AU - Qazi, Aamer AU - Seward, Shelly AU - Pal, Jagannath AU - Steffes, Christopher AU - Weaver, Donald AU - Morris, Robert AU - Malone, John AU - Shammas, Masood AU - Prasad, Madhu AU - Batchu, Ramesh PY - 2009/04/22/ UR - http://dx.doi.org/10.1186/1476-4598-8-26 ER -