Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the second-ranked cause of death among cancer patients. However, the mechanisms through which increased oxidative stress and inflammatory markers cause CRC are not well understood. Understanding these biochemical mechanisms, especially the role of increased reactive oxygen species (ROS) in the pathophysiology of CRC, will help in developing better therapeutic strategies. We have recently demonstrated that aldose reductase (AR) an enzyme that we have shown catalyzes the reduction of ROS- induced lipid aldehydes and their glutathione-conjugates (such as HNE and GS-HNE to DHN and GS-DHN), is an obligatory mediator of growth factor and cytokine-induced NF-?B activation in human colon cancer cells. Further, we have shown that AR inhibition or ablation by SiRNA prevents the growth of colon cancer cells in culture as well as in nude mice xenografts. Our long term goal is to understand the mechanisms by which AR contributes to CRC progression, and to develop AR inhibitors (ARIs) for chemoprevention of CRC. We will now systematically examine our hypothesis that the effects of ROS are in part mediated by AR- catalyzed reduced lipid peroxidation-derived aldehydes (LDAs) and their metabolites by investigating the role of AR in mediating growth factor-induced cancer growth in cultured cells, nude mice xenografts and murine models of CRC.
Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR inhibition in chemically and genetically-induced CRC in murine models. Completion of these studies should identify the molecular mechanisms of AR- reduced LDAs in mediating carcinogenic signals, and lead to use of AR inhibitors as excellent chemopreventive drugs for CRC.
HEALTH Relevance: colon cancer is the second leading cause of death among the cancer patients in US. Our project will determine the mechanisms of colon carcinogenesis, and ultimately lead to the development of new chemopreventive approaches to prevent death from colon cancer.
|Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2018) Aldose Reductase Inhibitor, Fidarestat Prevents High-fat Diet-induced Intestinal Polyps in ApcMin/+ Mice. Curr Cancer Drug Targets 18:905-911|
|Sonowal, Himangshu; Pal, Pabitra; Shukla, Kirtikar et al. (2018) Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction. Biochem Pharmacol 150:181-190|
|Awasthi, Sanjay; Tompkins, Joshua; Singhal, Jyotsana et al. (2018) Rlip depletion prevents spontaneous neoplasia in TP53 null mice. Proc Natl Acad Sci U S A 115:3918-3923|
|Awasthi, Yogesh C; Ramana, Kota V; Chaudhary, Pankaj et al. (2017) Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity. Free Radic Biol Med 111:235-243|
|Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish et al. (2017) Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells. Cancer Lett 411:57-63|
|Sonowal, Himangshu; Pal, Pabitra B; Wen, Jian-Jun et al. (2017) Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity. Sci Rep 7:3182|
|Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K et al. (2014) 4-Hydroxynonenal in the pathogenesis and progression of human diseases. Curr Med Chem 21:230-7|
|Li, Yang; Zhao, Zhongxin; Xu, Chuanhui et al. (2014) HMGA2 induces transcription factor Slug expression to promote epithelial-to-mesenchymal transition and contributes to colon cancer progression. Cancer Lett 355:130-40|
|Saxena, Ashish; Shoeb, Mohammad; Tammali, Ravinder et al. (2014) Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Cancer Lett 355:141-7|
|Shoeb, Mohammad; Ramana, Kota V; Srivastava, Satish K (2013) Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Radic Biol Med 63:280-90|
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