Advances in Cancer Biology - Metastasis (Dec 2021)
Incipient citrus polymethoxylated flavone Tangeretin as anticancer drug candidate: Mechanistic insights, limitations and possible solutions
Abstract
Tangeretin is one of the many polymethoxyflavones (PMFs) mostly found in fruits and fruit peels of citrus plants. In view of its importance as a nutraceutical it has received extensive scientific scrutiny with regards to its suspected diverse bioactivities including anti-oxidant, anti-diabetes, anti-inflammatory, neuroprotection, efflux pump inhibition, anti-microbial, and mitochondrial biogenesis just to mention but a few have been confirmed in both in vitro and in vivo studies. Importantly, tangeretin and other PMFs have demonstrated anti-cancer properties, which have stimulated renewed efforts among natural product scientists to explore the possibility of finding a natural anti-cancer template for development of diverse and readily available natural anti-cancer therapies. Nonetheless, current knowledge on the anti-cancer properties of tangeretin and other PMFs, particularly their natural sources, chemistry, pharmacokinetics, anti-cancer efficacy and most importantly their anti-cancer mechanisms remain limited. The current review provides an expanded overview of anti-cancer effects of tangeretin on many cancer subtypes, current knowledge, knowledge gaps, and future prospects. Specifically, the review highlights interaction of tangeretin with cell signaling pathways implicated in inflammation-related cancers and hormone-sensitive cancers as well as their downstream mediators. Information on tangeretin and PMFs in major electronic scientific databases including Scopus, Web of science, Web of science core collection, PubMed, PubMed central, just to mention but a few were accessed. Pre-clinically, tangeretin has enjoyed extensive scientific scrutiny, however, it was sad to discover that the quantum of pre-clinical data on tangeretin could not translate into a strong rationale for clinical trial on tangeretin or other PMFs either as monotherapy or as a combination with conventional chemotherapeutics. Although, tangeretin has low oral bioavailability but it was encouraging to find many studies exploring new tangeretin formulations and other improved drug delivery strategies. Tangeretin per current knowledge demonstrates a wide and diverse spectrum of bioactivities crucial for cancer pharmacotherapy. Tangeretin ameliorated most of the key hallmarks of cancer in various cancer subtypes through diverse signaling pathways and mediators including PI3K/Akt/Mtor, JNK/Bcl-2/BECLIN1, MAPK, Wnt/B-catenin, cyclin B1, p53, p27 and p21, activation of Caspase-3, Bad, and Bax proteins while decreasing anti-apoptotic factors (Bcl-2, Bcl-xL), prostate specific antigen, and mitochondrial membrane potential. The volume of pre-clinical data on tangeretin provides a compelling rationale for clinical trials to be initiated on tangeretin either as a monotherapy or as a combination with conventional chemotherapeutics.
