Exploring the chemotherapeutic potential and therapeutic insight of phloretin against human malignancies: a systematic review

The search of alternative therapeutic agents for the use  of cancer patients has dramatically expanded. Natural products are especially in focus since their structures already function in nature and are more likely to be potent with fewer side effects. Phloretin is a natural product that has been studied for a wide variety of pharmacological actions against human malignancies. This systematic review aims to present up-to-date critical and comprehensive information on the anti-cancer ability of Phloretin with all associated molecular and cellular mechanisms in various forms of cancers. Data retrieved according to PRISMA guidelines from Science Direct, PubMed, and Scopus searching servers by using keywords including Phloretin, cancer name, synergistic, resistance and Pharmacokinetics property was analyzed via some in silico tools. This systematic review comprised 127 articles from different types of study, where Phloretin is hypothesized to be effective against 20 various forms of cancer. Phloretin has been found to inhibit cancer initiation and progression by modulating many imbalanced signalling pathways, including apoptosis, autophagy, necrosis, metastasis, angiogenesis, cell proliferation, glucose absorption, oxidative stress, inflammation, DNA damage, and many other pathways. This wide range of activity may be due to the structural targeting of numerous proteins including, Bcl-2, Bax, Bak, Bad, caspase, cyclins (B1, D1, E) and CDKs (4, 6,7) p18, p21, p27, p53, MMP-2, MMP- 8, MMP-9, Wnt/-catenin, PARP, TNF-α, NF-κB, IκB kinase, IL-1β, TNF-α, phospho-Akt, phosphor-p65, NF-κB, PI3K/Akt, MAPK/ERK, p-mTOR. The introduction of nano-technology-based strategies can improve the efficacy of Phloretin for cancer treatment. Existing evidence shows that Phloretin has synergistic effects with other natural compounds and conventional drugs, and this mechanism assists in reversing the resistance of anticancer drugs by regulating resistance-related proteins. However, Phloretin possesses favorable pharmacokinetic properties with  low toxicity in the human body by in silico methods. Therefore, Phloretin could be a potential anti-cancer drug against numerous cancer treatment by mitigating it's toxic effect and enhancing efficacy using nano-technology-based strategies.