There is an increased interest in the scientific community on the use of plant based polyphenols. An important advantage with plant based polyphenols, especially those from dietary sources, is that they are perceived as non-toxic and have wide human acceptance. Flavonoids are a large family of polyphenolic macronutrients.In laboratory studies flavonoids have been shown to influence cell survival and proliferation.
In this study the authors evaluated the effects of fisetin against melanoma and cancers of the prostate, pancreas and the lungs. Using prostate and lung adenocarcinoma cells, it was observed that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding because mTOR’s activation is more frequent in tumors with overexpression of the PI3K/Akt pathways. Because of that dual inhibition of PI3K/Akt and mTOR signaling is suggested as agent for treating such cancers. The observatios made in the study, inline with findings from other laboratories, suggest that fisetin could be a useful chemotherapeutic agent that could be used either alone or as an adjuvant with conventional chemotherapeutic drugs for the management of prostate and other cancers.
In more detail the mTOR pathway drives a feedback loop and keeps the PI3K/Akt activity under tight control. One consequence of mTOR inhibition is alleviation of this negative feedback loop resulting in activation of PI3K and subsequent activation of Akt. Therefore, simultaneously targeting of both PI3K/Akt and mTOR has the potential to inhibit both upstream and downstream signaling in the pathway. By physically interacting with the mTOR molecule and inhibiting its activity, fisetin treatment of human prostate cancer cells inhibits mTOR signaling both upstream and downstream. Additionally, fisetin also inhibits the PI3K/Akt pathway which ensures that the feedback loop remains in check. Our findings suggest that fisetin inhibits the mTOR pathway in addition to inhibition of the PI3K/Akt pathway. In addition fisetin has been shown to enhance cytotoxic effects when combined with other known chemotherapeutic drugs. Fisetin also sensitized TRAIL-resistant androgen-dependent LNCaP and the androgen-independent DU145 and PC3 prostate cancer cells to TRAIL-induced death. These observation sunderscore the importance of testing fisetin in combination with known and conventional chemotherapeutic drugs. Therefore, based on these observations fisetin could be developed as a novel agent for the management of prostate cancer.
The wide ranging study can be found here.