Development of novel anti-cancer agents based on cytochrome P-450-mediated epoxides of Omega-3 fatty acids - GNT1087248

Project Member(s): Rawling, T.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC Project Grants)

Start year: 2015

Summary: Breast cancer is the second leading cause of cancer-related deaths with 15,000 women diagnosed annually. Despite improvements in drug therapy many patients experience toxicity or low efficacy, which prevents successful outcomes. When breast cancers reach an advanced stage most treatment options have been exhausted. Accordingly, there is an urgent need for new cancer drugs. Epidemiological studies have shown that dietary omega-3 polyunsaturated fatty acids (PUFAs) decrease breast cancer progression. This finding is supported by experimental studies where omega-3 PUFAs inhibit the proliferation of migration of breast cancer cells in vitro. PUFAs elicit biological responses by metabolic conversion to active signaling molecules, and we recently identified an omega-3 epoxide metabolite that inhibits tumour cell proliferation by down-regulating cyclin D1 and activates apoptotic cell death. The epoxide is not a suitable drug candidate due to its instabililty. Using drug stabilistaion strategies, we developed novel and stable omega-3 epoxide analogues that kill breast cancer cells in vitro and in xenograft models in vivo, with no evidence of toxicity. The overall aim of this current project is to develop optimal analogues that may be developed into new anticancer agents. We will identify the mode of action of our new agents, and optimize their antiproliferative and pharmacokinetic properties, which will be assessed in animal models of breast cancer.

Publications:

Rahman, MK, Umashankar, B, Choucair, H, Bourget, K, Rawling, T & Murray, M 2024, 'The inositol-requiring enzyme 1 (IRE1) endoplasmic reticulum stress pathway promotes MDA-MB-231 cell survival and renewal in response to the aryl-ureido fatty acid CTU', The International Journal of Biochemistry & Cell Biology, vol. 171, pp. 106571-106571.
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Rawling, T, MacDermott-Opeskin, H, Roseblade, A, Pazderka, C, Clarke, C, Bourget, K, Wu, X, Lewis, W, Noble, B, Gale, PA, O'Mara, ML, Cranfield, C & Murray, M 2020, 'Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter', Chemical Science, vol. 11, no. 47, pp. 12677-12685.
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Al-Zubaidi, Y, Pazderka, C, Koolaji, N, Rahman, MK, Choucair, H, Umashankar, B, Bourget, K, Chen, Y, Rawling, T & Murray, M 2019, 'Aryl-urea fatty acids that activate the p38 MAP kinase and down-regulate multiple cyclins decrease the viability of MDA-MB-231 breast cancer cells', European Journal of Pharmaceutical Sciences, vol. 129, pp. 87-98.
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Rahman, MK, Rawling, T, Al-Zubaidi, Y, Choucair, H, Umashankar, B, Chen, Y, Bourget, K, Tam, S, Smith, C & Murray, M 2019, 'Abstract A119: Inhibition of IRE1-mediated pro-tumorigenic responses enhances the sensitivity of MDA-MB-231 cells to the novel arylurea-fatty acid CTU', Molecular Cancer Therapeutics, vol. 18, no. 12_Supplement, pp. A119-A119.
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Koolaji, N, Rawling, T, Bourget, K & Murray, M 2018, 'Carboxylate Analogues of Aryl‐Urea‐Substituted Fatty Acids That Target the Mitochondria in MDA‐MB‐231 Breast Cancer Cells to Promote Cell Death', ChemMedChem, vol. 13, no. 10, pp. 1036-1043.
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Dyari, HRE, Rawling, T, Chen, Y, Sudarmana, W, Bourget, K, Dwyer, JM, Allison, SE & Murray, M 2017, 'A novel synthetic analogue of ω‐3 17,18‐epoxyeicosatetraenoic acid activates TNF receptor‐1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells', The FASEB Journal, vol. 31, no. 12, pp. 5246-5257.
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Rawling, T, Choucair, H, Koolaji, N, Bourget, K, Allison, SE, Chen, Y-J, Dunstan, CR & Murray, M 2017, 'A Novel Arylurea Fatty Acid That Targets the Mitochondrion and Depletes Cardiolipin To Promote Killing of Breast Cancer Cells', Journal of Medicinal Chemistry, vol. 60, no. 20, pp. 8661-8666.
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Murray, M, Choucair, H, Allison, S, Bourget, K, Chen, Y, Dunstan, C & Rawling, T 2017, 'O25 A novel synthetic ω-3 fatty acid epoxide analogue activates breast cancer cell killing in vitro and in vivo', Elsevier BV, pp. 117-117.
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Koolaji, N, Murray, M & Rawling, T 2016, 'Aryl group modification in novel anti-cancer agents based on ω-3-17,18-epoxyeicosapentaenoic acid', Elsevier BV, pp. S68-S68.
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Keywords: breast cancer, omega-3 polyunsaturated fatty acids, epoxides, drug development.

FOR Codes: Pharmacology and Pharmaceutical Sciences, Cancer and Related Disorders, Clinical health

Acknowledgement of Country

UTS acknowledges the Gadigal people of the Eora Nation, the Boorooberongal people of the Dharug Nation, the Bidiagal people and the Gamaygal people, upon whose ancestral lands our university stands. We would also like to pay respect to the Elders both past and present, acknowledging them as the traditional custodians of knowledge for these lands.