The Anti-cancer Effects of Chemically Synthesized Flavokawain B on MCF-7 and MDA-MB231 Cells In Vitro, and 4T1 Cells In Vivo
By: Dr. Nadiah Abu (nadiah.abu@ppukm.ukm.edu.my)
Drug discovery of novel anti-cancer agents has been carried out for many decades. Several prominent drugs used in cancer treatment have been derived from natural sources, namely, doxorubicin, docetaxel and taxol. It is estimated that around~49% of entities or drugs used for cancer treatment were derived from natural-based products. Several different classes of molecules possess anti-cancer activity such as taxanes, anthraquinones, anthracyclines and flavonoids. We decided to embark on a project that utilizes 鈥渃halcones鈥 in the search of a promising anti-cancer agent. Chalcones are becoming the favourite for medicinal chemists due to its simple design, ease of synthesis and due to the fact that chalcones can produce a large number of derivatives. We selected Flavokawain B (FKB) for further studies as it has the most promising bioactivity. FKB is a chalcone that can be either be extracted from Piper methysticum or synthesized using the Claisen-Shcmidt condensation method. Additionally, FKB fulfils all the requirements of drug 鈥渓ikeliness鈥 as outlined by the Lipinski鈥檚 Rule of 5. Toxicity assessment of FKB was performed using Balb/C mice, where no toxicity was observed after 28 days of treatment with 50 mg/kg FKB. We further elucidated FKB鈥檚 anti-cancer mechanism using in vitro studies on MCF-7 and MDA-MB231 breast cancer cell lines. FKB managed to induce apoptosis in both cell lines as evidenced by MTT, BrdU, cell cycle, annexin V and mitchondrial membrane potential assays. Moreover, FKB also successfully reduced the number of tubes formed in HUVEC cells as well as in a rat aortic ring assay. FKB was found to reduce the expression of several pro-metastatic genes and proteins such as VEGF and CXCR4. We then proceeded with in vivo studies using a 4T1 mouse breast cancer model. After 28 days of treatment, FKB significantly reduced the size and weight of the 4T1 tumors. Additionally, FKB also inhibited the migration of the 4T1 cells to the lungs, livers, and spleens of the tested mice. Overall, FKB exhibited promising anti-cancer effects based on preliminary tests performed. However, further studies in terms of pharmacodynamics, pharmacokinetics as well as biodistribution should be conducted to further illuminate FKB鈥檚 potential as an anti-cancer agent.