Marine life has provided mankind with unique and extraordinary chemical structures and scaffolds with potent biological activities. Many organisms and secondary metabolites derived from fungi and symbionts are found to be more environmentally friendly to study than the marine corals per se. Marine symbionts such as Aspergillus sp., a fungus, which can be isolated and grown in the lab would be a potential and continuous source of bioactive natural compounds without affecting the marine environment. The Red Sea is known for its biodiversity and is well-studied in terms of its marine-derived bioactive metabolites. The harsh environmental conditions lead to the development of unique metabolic pathways. This, in turn, results in enhanced synthesis and release of toxic and bioactive chemicals. Interestingly, the Persian Gulf and the Gulf of Oman carry a variety of environmental stresses, some of which are similar to the Red Sea. When compared to the Red Sea, the Persian Gulf has been shown to be rich in marine fungi as well, and is, therefore, expected to contain elaborate and interesting bioactive compounds. Such compounds may or may not be similar to the ones isolated from the Red Sea environment. Astoundingly, there are a very limited number of studies on the bioactive portfolio of marine-derived metabolites from the Persian Gulf and the Gulf of Oman. In this perspective, we are looking at the Red Sea as a comparator marine environment and bioactive materials repertoire to provide a futuristic perspective on the potential of the understudied and possibly overlooked bioactive metabolites derived from the marine life of the Persian Gulf and the Gulf of Oman despite its proven biodiversity and harsher environmental stress.
Background: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and therefore, treatment failure. Methods: The potential anticancer properties of terrein, its antiproliferative effects, and its chemomodulatory effects on GCB were assessed against various colorectal cancer cell lines (HCT-116, HT-29, and SW620) under normoxic and hypoxic (pO2 ≤ 1%) conditions. Further analysis via flow cytometry was carried out in addition to quantitative gene expression and 1HNMR metabolomic analysis. Results: In normoxia, the effect of the combination treatment (GCB + Terr) was synergistic in HCT-116 and SW620 cell lines. In HT-29, the effect was antagonistic when the cells were treated with (GCB + Terr) under both normoxic and hypoxic conditions. The combination treatment was found to induce apoptosis in HCT-116 and SW620. Metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling. Conclusions: Terrein influenced GCB’s anti-colorectal cancer properties which are reflected in different aspects such as cytotoxicity, cell cycle progression, apoptosis, autophagy, and intra-tumoral metabolism under normoxic and hypoxic conditions.
Several semisynthetic analogs of camptothecin (CPT) are used clinically for the treatment of various types of cancers, including colorectal (CRC) cancer, despite their severe, potentially life-threatening toxicities. Studies defined key mutations in the UDP-glycosyltransferase 1 polypeptide A1 (UGT1A1) gene in CRC which play a role in the toxicity and resistance of a broad class of anti-cancer drugs that target DNA topoisomerases. UGT-1A1 is responsible for the glucuronidation and detoxification of the active/toxic metabolite of the topoisomerase I poison, CPT and its analogues, SN-38. Herein, we investigated the potential chemomodulatory effects of a UGT1A1-gene inducer, phenytoin, to the anticancer properties of CPT. The cytotoxic effects of CPT, phenytoin and their combination were evaluated against various colorectal cancer cell lines (SW620, HT29 and HCT116) using sulforhodamine-B assay under normoxic and hypoxic conditions. In HT29, CPT alone and after combination treatment had IC50’s of 0.1235 µM and 0.0269 µM, respectively, under normoxic conditions; and 0.1352 µM and 0.0476 µM, respectively, under hypoxic conditions. In SW620, CPT alone and after combination treatment had IC50’s of 1.9861 µM and 0.0087 µM, respectively, under normoxic conditions; and 1.9549 µM and 0.0024 µM, respectively, under hypoxic conditions. In HCT116, CPT alone and after combination treatment had IC50’s of 0.163 µM and 0.0157 µM, respectively, under normoxic conditions; and 0.1013 µM and 0.0766 µM, respectively, under hypoxic conditions. Flow cytometric analysis after annexin-V/FITC staining showed that the combination treatment significantly induced total apoptosis in all cell lines under investigation. In both HT29 and SW620, the combination treatment significantly suppressed the autophagy compared to CPT treatment alone using acridine orange staining coupled with flowcytometry. Cell cycle analysis using DNA content flowcytometry after PI staining showed significant S-phase arrest in the combination treatment when compared to the control across all cell lines under investigation. This indicates that sub-molecular mechanisms of phenytoin induced chemomodulatory effect to CPT anticancer properties is oxygen tension dependent. Further investigation for the intratumoral metabolism of CPT under hypoxic as well as normoxic conditions and particularly those attributed to UGT-1A1 is currently undergoing. Citation Format: Dalia Al Saeedy, Reham K. Abuhijjleh, Ahmed Gouda, Sherif F. El-Khamisy, Ahmed M. Al-Abd. Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1049.
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