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Exploring Novel Cancer Targets Unveiled by Established Nsaids
Corresponding Author(s) : Ramsiya K
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 12 No. 3 (2024): 2024 Volume -12 - Issue 3
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly selective inhibitors of cyclooxygenase-2 (COX-2), have emerged as promising candidates for their potential to combat cancer. Epidemiological, clinical, and preclinical investigations have consistently demonstrated their association with a reduced incidence of various cancers, including colorectal, lung, esophageal, pancreatic, cervical, skin, and ovarian cancers. However, the clinical application of traditional NSAIDs is hindered by gastrointestinal adverse effects. Selective COX-2 inhibitors offer improved gastrointestinal profiles, sparking interest in their role as chemopreventive agents. Yet, uncertainties persist regarding whether the anticancer effects of NSAIDs solely stem from COX inhibition or involve COX-independent mechanisms.
This review aims to delineate the anticancer mechanisms of NSAIDs, focusing on aspirin and similar agents, while exploring avenues for enhancement. Mechanistic insights suggest potential targets beyond COX enzymes, such as phosphodiesterase-5 (PDE5) inhibition, leading to apoptosis induction. Additionally, advancements in medicinal chemistry propose novel strategies, including aspirin prodrugs, nitroaspirin, NF-κB inhibitors, and modified sulindac derivatives, for targeted cancer therapy. Furthermore, 2-arylpropionic acid-derived NSAIDs have demonstrated antiproliferative effects across various cancer cell lines, highlighting their potential as lead compounds for potent and safe anticancer agents.
Despite these advancements, further research is warranted to elucidate precise mechanisms of action, optimize treatment regimens, and evaluate risk-benefit ratios. By advancing our understanding of NSAIDs in cancer prevention and treatment, we can potentially revolutionize cancer care paradigms.
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- Piazza GA, Keeton AB, Tinsley HN, Whitt JD, Gary BD, Mathew B, Singh R, Grizzle WE, Reynolds RC. NSAIDs: old drugs reveal new anticancer targets. Pharmaceuticals. 2010 May 25;3(5):1652-67.
- Zhang Z, Chen F, Shang L. Advances in antitumor effects of NSAIDs. Cancer management and research. 2018 Oct 15:4631-40.
- Marks F, Fürstenberger G. Cancer chemoprevention through interruption of multistage carcinogenesis: the lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer. European Journal of Cancer. 2000 Feb 1;36(3):314-29.
- Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, Subbaramaiah K. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. The lancet oncology. 2001 Sep 1;2(9):544-51.
- Gardiner, P.S. and Gilmer, J.F. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini Reviews in Medicinal Chemistry, 2023; 3(5), pp.461-470.
- Nzeako, U.C., Guicciardi, M.E., Yoon, J.H., Bronk, S.F. and Gores, G.J. COX‐2 inhibits Fas‐mediated apoptosis in cholangiocarcinoma cells. Hepatology, 2002; 35(3):552-559.
- Zimmermann, K.C., Sarbia, M., Weber, A.A., Borchard, F., Gabbert, H.E. Schror, K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer research, 1999; 59(1):198-204.
- Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
- Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. Journal of the National Cancer Institute. 2002 Feb 20;94(4):252-66.
- Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
- Fujita T, Matsui M, Takaku K, Uetake H, Ichikawa W, Taketo MM, Sugihara K. Size-and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer research. 1998 Nov 1;58(21):4823-6.
- Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer research. 1999 Jan 1;59(1):198-204.
- Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer control. 2002 Mar;9(2_suppl):28-35.
- Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
- Piazza GA, Keeton AB, Tinsley HN, Whitt JD, Gary BD, Mathew B, Singh R, Grizzle WE, Reynolds RC. NSAIDs: old drugs reveal new anticancer targets. Pharmaceuticals. 2010 May 25;3(5):1652-67.
- Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. Journal of the National Cancer Institute. 2002 Feb 20;94(4):252-66.
- Gardiner PS, Gilmer JF. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini Reviews in Medicinal Chemistry. 2003 Aug 1;3(5):461-70.
- Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
- Özdemir Ö, Marinelli L, Cacciatore I, Ciulla M, Emsen B, Di Stefano A, Mardinoglu A, Turkez H. Anticancer effects of novel NSAIDs derivatives on cultured human glioblastoma cells. Zeitschrift für Naturforschung C. 2021 Jul 27;76(7-8):329-35.
References
Piazza GA, Keeton AB, Tinsley HN, Whitt JD, Gary BD, Mathew B, Singh R, Grizzle WE, Reynolds RC. NSAIDs: old drugs reveal new anticancer targets. Pharmaceuticals. 2010 May 25;3(5):1652-67.
Zhang Z, Chen F, Shang L. Advances in antitumor effects of NSAIDs. Cancer management and research. 2018 Oct 15:4631-40.
Marks F, Fürstenberger G. Cancer chemoprevention through interruption of multistage carcinogenesis: the lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer. European Journal of Cancer. 2000 Feb 1;36(3):314-29.
Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, Subbaramaiah K. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. The lancet oncology. 2001 Sep 1;2(9):544-51.
Gardiner, P.S. and Gilmer, J.F. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini Reviews in Medicinal Chemistry, 2023; 3(5), pp.461-470.
Nzeako, U.C., Guicciardi, M.E., Yoon, J.H., Bronk, S.F. and Gores, G.J. COX‐2 inhibits Fas‐mediated apoptosis in cholangiocarcinoma cells. Hepatology, 2002; 35(3):552-559.
Zimmermann, K.C., Sarbia, M., Weber, A.A., Borchard, F., Gabbert, H.E. Schror, K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer research, 1999; 59(1):198-204.
Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. Journal of the National Cancer Institute. 2002 Feb 20;94(4):252-66.
Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
Fujita T, Matsui M, Takaku K, Uetake H, Ichikawa W, Taketo MM, Sugihara K. Size-and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer research. 1998 Nov 1;58(21):4823-6.
Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer research. 1999 Jan 1;59(1):198-204.
Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer control. 2002 Mar;9(2_suppl):28-35.
Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
Piazza GA, Keeton AB, Tinsley HN, Whitt JD, Gary BD, Mathew B, Singh R, Grizzle WE, Reynolds RC. NSAIDs: old drugs reveal new anticancer targets. Pharmaceuticals. 2010 May 25;3(5):1652-67.
Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. Journal of the National Cancer Institute. 2002 Feb 20;94(4):252-66.
Gardiner PS, Gilmer JF. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini Reviews in Medicinal Chemistry. 2003 Aug 1;3(5):461-70.
Gouda AM, Beshr EA, Almalki FA, Halawah HH, Taj BF, Alnafaei AF, Alharazi RS, Kazi WM, AlMatrafi MM. Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action. Bioorganic Chemistry. 2019 Nov 1;92:103224.
Özdemir Ö, Marinelli L, Cacciatore I, Ciulla M, Emsen B, Di Stefano A, Mardinoglu A, Turkez H. Anticancer effects of novel NSAIDs derivatives on cultured human glioblastoma cells. Zeitschrift für Naturforschung C. 2021 Jul 27;76(7-8):329-35.