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Terrein is a bioactive marine secondary metabolite isolated from the fungal strain of Penicillium species SF-7181 and Aspergillus terreus. Previous studies showed that terrein possesses cytotoxic properties attributed to interrupting various molecular pathways, such as nuclear factor kappa B (NF-kB). Gemcitabine (GCB) is an anticancer drug commonly used to treat colorectal cancer; however, it suffers from tumor cell resistance and subsequently treatment failure. In this study, the potential anticancer properties of terrein as well as its chemomodulatory effect on GCB are assessed against various colorectal cancer cell lines (SW620, HT29 and HCT116) under normoxic and hypoxic (pO2 ≤ 1%) conditions. The antiproliferative effects of terrein, GCB and their equitoxic combination were evaluated using sulforhodamine-B assay. In SW620, terrein had IC50’s of 66.89±8.5 µM and 73.4±1.3 µM as single treatment, and the IC50’s of GCB in combination treatment were 0.27± 0.01 µM and 0.24±0.04 µM, under hypoxic and normoxic conditions, respectively. In HT29, terrein had IC50’s of 85.5±4.4 µM and 49.6±11.4 µM, and the IC50’s of GCB in combination treatment were 3.2±0.08 µM and 0.27±0.005 µM, under hypoxic and normoxic conditions, respectively. In HCT116, terrein had IC50’s of 21.6±2.891 µM and 74.76±0.97 µM, and the IC50’s of GCB in combination treatment were 0.23±0.03 µM and 0.23±0.005 µM, under hypoxic and normoxic conditions, respectively. In both SW620 and HCT116, terrein exhibited a preferential antitumor effect in hypoxic conditions; however, the opposite was observed in HT29. Upon further analysis via flow cytometry after annexin-V/FITC and PI staining, GCB and its combination treatment with terrein were found to induce necrosis in all cell lines under investigation. In addition, terrein was found to significantly induce significant S-phase cell arrest compared to GCB treatment alone using DNA content cytometry assay coupled with PI staining. Currently, we are studying the expression of multiple cyclins/CDK’s involved in the different cell cycle phases for further understanding of the detailed mechanism of action. Using flowcytometry assessment after staining with acridine orange, terrein suppressed autophagy compared to control cells as well as GCB treatment. NMR metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling such as leucin, which increased significantly due to hypoxia; while tyrosine decreased significantly in response to hypoxic environment. Currently, the gene expression profiling corresponding to these amino acids metabolomic changes are undergoing. Therefore, oxygen concentration plays a vital role in the intratumoral amino acid metabolism in response to terrein, GCB and their combination within colorectal cancer cells. Citation Format: Reham K. Abu Hijjleh, Dalia Y. Al Saeedy, Naglaa S. Ashmawy, Ahmed Gouda, Sameh S. Elhady, Ahmed M. Al-Abd. The potential chemo-modulatory effect of the marine-derived secondary metabolite terrein on the anticancer properties of gemcitabine in colorectal cancer cells [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 1065.