Anti-tumor effects of sea cucumber extract and investigation of synergistic interaction with traditional chemotherapic drugs

Cancer is one of the major health problems in the world, characterized by uncontrolled proliferation of cells. Therefore, the development of both safe and effective anticancer agents is inevitable. The main concern in cancer treatment is the toxic effect of the developed drugs. Most attempts have been directed to the search for synergistically effective nutrient sources and phytotherapeutic agents in combination with anti-cancer drugs. The combination of extracts from plant or marine organisms with conventional chemotherapeutic agents increases the efficacy in cancer treatment. It is known that there is significant potential for the identification of new anti-cancer compounds from different geographic regions and different species of cucumber. Therefore, the main aim of this study was to investigate anti-tumor effects of extracts from a sea cucumber species Holothuria sanctori collected from Gökova Bay on various cancer cells and to investigate the synergistic effects of these extracts with commercial cancer drugs (cisplatin, docetaxel) in use. The cytotoxic effects and mechanisms of Holothuria sanctori extracts prepared with acetone and methanol on A549 and PC-3 cells were investigated. When the cytotoxic activities of HSM and HSA extracts in 24, 48 and 72 hours incubation periods were examined according to dose and time; The cytotoxic effect of Holothuria sanctori acetone and methanol extracts on A549 cells varies depending on dose and time; the most effective dose – time paired for 72 hours and 20 mg/ml. Furthermore, HSA (1.7 mg/ml) showed a higher effect at lower doses when IC50 values were compared after 72 hours incubation, where both extracts were most effective. For the PC-3 cell line; it can be said that the extracts prepared with HSM and HSA have increased cytotoxic effects over time. The healthy cell line HEK293; the cytotoxic effects of HSM and HSA extracts were found to be less than those of PC-3 and A549. It was determined by using flow cytometry method using Annexin V that HSM extract drains A549 cells to apoptosis. Apoptotic cell death was observed in PC-3 cancer cells exposed to different concentrations of HSM extract. The caspase-3 activity in A549 cells was approximately 2.1-fold compared to control cells; PC-3 cells increased 1.9 fold. It can be said that the HSM extract induces apoptosis in the A549 and PC-3 cell line and is consistent with the data obtained from flow cytometry analysis and MTT assay results. When the interaction of HSA and HSM extracts of Holothuria sanctori with cisplatin and docetaxel, which are widely used in cancer treatment, are examined; all interactions were found to be antagonistic. HPLC analysis revealed phenolic compounds in the HSM extract. According to this analysis, the most common phenolic compounds in the HSM extract are ellagic acid and epicatechin. Future studies will identify the mechanism of effects of each compound on these cancer cells. In conclusion, this is the first study elucidating the cytotoxic effects of Holothuria sanctori which has a high economic value and is widespread in the seas of our country.