Mammalian target of Rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, motility and survival. Acting downstream of AKT, also a serine kinase, mTOR is composed of the mTORC1-Raptor complex and the mTORC2-Rictor complex. mTOR has been implicated in many cancers, including ovarian cancer, due to the effect of mTOR inhibitors on tumor progression. In addition, mTORC2 has a positive feedback effect on AKT behavior, which may explain its rapamycin resistance. Rapamycin is a common drug used as a targeted therapy for mTOR inhibition, however it is not successful in all cancer types. In Ovarian Cancer specifically, the PI3K/AKT/mTOR pathway is the most frequently altered pathway, with PI3K, AKT and mTOR expression levels correlating with survival and tumor growth. In the following articles, an mTOR antibody is used to investigate the efficacy of two potential therapies different from the traditional rapamycin approach to human ovarian cancer.
In the first article, Mabuchi et al used an mTOR antibody in their research to investigate the therapeutic role of mTOR may have in cisplatin-sensitive and cisplatin-resistant ovarian cancer. Cisplatin, a chemotherapeutic agent, is not entirely effective in treating ovarian cancer; therefore, alternative treatment methods are needed. This group employed the use of a powerful experimental technique known as a tissue microarray to screen nearly 100 tissue samples from both clear cell carcinoma and serous adenocarcinoma ovarian cancer types with an mTOR antibody (among others). Specifically, a phospho-mTOR antibody was used to measure the expression level of phosphorylated mTOR in these samples. To follow, cisplatin-sensitive cells (RMG1,KOC7C) and cisplatin-resistant cells (RMG1-CR, KOC7C-CR) were analyzed for growth inhibition in response to a block in mTOR using RAD001. Their results concluded that mTOR was highly activated in clear cell ovarian cancer carcinomas over serous adenocarcinomas and that inhibition with RAD001 slowed the growth of both cell lines tested. These results indicate a promising future for mTOR-targeted therapies in cancers resistant to chemotherapy.
In an entirely different approach, Han et al experimented with the effects of a traditional Chinese herbal formula “Guizhi Fuling Wan (GFW)” in sensitizing cisplatin resistant human ovarian cancer cells through alterations in the PI3K/AKT/mTOR pathway using an mTOR antibody. Similar to Mabuchi’s group, Han set out to determine an alternative treatment option for patients who are desensitized to traditional cisplatin chemotherapeutic management. Using an mTOR antibody in western blot, they found that medicated Rat sera exposed to GFW inhibited drug resistance involved in the PI3K/AKT/mTOR signaling pathway. Specifically, SKOV3/DDP cells (which are resistant to chemotherapeutic agents) were treated for 72 hours with GFW, lysed and analyzed for mTOR, p-AKT, AKT and PI3K activity using primary antibodies. What’s more, incubation of SKOV3/DDP cell lines in vitro with GFW restored cell sensitive to cisplatin. Overall, this study shows that GFW is successful at inhibiting P-gp expression, which is orchestrated by the PI3K/AKT/mTOR pathway.
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