Shailender Kanwar

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• EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine.

  Authors: Jyoti Nautiyal, Jinhua Du, Yingjie Yu, Shailender S. Kanwar, Edi Levi, Adhip P.N. Majumdar

  AJP Gastrointestinal and Liver Physiology.

• MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFβR2) in colon cancer cells.

  Authors: Yingjie Yu, Shailender S Kanwar, Bhaumik B Patel, Phil-Sun Oh, Jyoti Nautiyal, Fazlul H Sarkar, Adhip P N Majumdar

  Carcinogenesis.

  Although microRNA-21 (miR-21) is emerging as an oncogene and has been shown to target several tumor-suppressor genes, including programmed cell death 4 (PDCD4), its precise mechanism of action onAlthough microRNA-21 (miR-21) is emerging as an oncogene and has been shown to target several tumor-suppressor genes, including programmed cell death 4 (PDCD4), its precise mechanism of action on cancer stem cells (CSCs) is unclear. Herein, we report that FOLFOX-resistant HCT-116 and HT-29 cells that are enriched in CSCs show a 3-7 fold up-regulation of pre- and mature miR-21 and down-regulation of PDCD4. Likewise, over-expression of miR-21 in HCT-116 cells, achieved through stable transfection, led to down-regulation of PDCD4 and TGFβR2. In contrast, the levels of β-catenin, TCF/LEF activity and the expression of c-Myc, Cyclin-D, which are increased in CSCs, are also augmented in miR-21 overexpressing colon cancer cells, accompanied by an increased sphere forming ability in vitro and tumor formation in SCID mice. Down-regulation of TGFβR2 could be attributed to decreased expression of the receptor as evidenced by reduction in the activity of the luciferase gene construct comprising of TGFβR2-3'UTR sequence that binds to miR-21. Moreover, we observed that downregulation of miR-21 enhances luciferase-TGFβR2-3'UTR activity suggesting TGFβR2 as being one of the direct targets of miR-21. Further support is provided by the observation that transfection of TGFβR2 in HCT-116 cells attenuates TCF/LEF luciferase activity, accompanied by decreased expression of β-catenin, c-Myc and Cyclin-D1. Our current data suggest that miR-21 plays an important role in regulating stemness by modulating TGFβR2 signaling in colon cancer cells.

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• Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells.

  Authors: Jyoti Nautiyal, Shailender S Kanwar, Yingjie Yu, Adhip Pn Majumdar

  Journal of molecular signaling. 6(1):7.

  ABSTRACT: Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy forABSTRACT: Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APCMin +/- mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APCMin +/- mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.

• Schlafen-3 decreases cancer stem cell marker expression and autocrine/ juxtacrine signaling in FOLFOX-resistant colon cancer cells.

  Authors: Phil-Sun Oh, Vaishali B Patel, Matthew A Sanders, Shailender S Kanwar, Yingjie Yu, Jyoti Nautiyal, Bhaumik B Patel, Adhip P N Majumdar

  American journal of physiology. Gastrointestinal and liver physiology.

  We have previously demonstrated that expression of the novel gene schlafen (Slfn)-3 correlates with intestinal epithelial cell differentiation. The current investigation was undertaken to examineWe have previously demonstrated that expression of the novel gene schlafen (Slfn)-3 correlates with intestinal epithelial cell differentiation. The current investigation was undertaken to examine whether Slfn-3 plays a role in regulating differentiation of FOLFOX-resistant (5-Fluorouracil + oxaliplatin) colon cancer cells that are highly enriched in cancer stem cells (CSCs). Transfection of Slfn-3 in FOLFOX-resistant colon cancer HCT-116 cells resulted in increase of alkaline phosphatase (ALP) activity, a marker of intestinal differentiation. Additionally, Slfn-3 transfection resulted in reduction of mRNA and protein levels of the CSC markers CD44, CD133, CD166, and aldehyde dehydrogenase 1 (ALDH1) in both FOLFOX-resistant HCT-116 and HT-29 cells. This was accompanied by decreased formation of tumorosphere/colonosphere (an in vitro model of tumor growth) in stem cell medium and inhibition of expression of the chemotherapeutic drug transporter protein ABCG2. Additionally, Slfn-3 transfection of FOLFOX-resistant HCT-116 and HT-29 cells reduced Hoechst 33342 dye exclusion. Finally, Slfn-3 transfection inhibited the expression of transforming growth factor-α (TGF-α) in both FOLFOX-resistant colon cancer cells but stimulated apoptosis in response to additional FOLFOX treatment. In summary, our data demonstrate that Slfn-3 expression inhibits multiple characteristics of CSC-enriched FOLFOX-resistant colon cancer cells including induction of differentiation and reduction in tumorosphere/colonosphere formation, drug transporter activity and autocrine stimulation of proliferation. Thus, Slfn-3 expression may render colon CSCs more susceptible to cancer chemotherapeutics.

• Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells.

  Authors: Jyoti Nautiyal, Sanjeev Banerjee, Shailender S Kanwar, Yingjie Yu, Bhaumik B Patel, Fazlul H Sarkar, Adhip P N Majumdar

  International journal of cancer. Journal international du cancer. 128(4):951-61.

  Colorectal cancer is the third most common form of malignancy, behind prostate and lung cancers. Despite recent advances in medicine, mortality from colorectal cancer remains high, highlighting theColorectal cancer is the third most common form of malignancy, behind prostate and lung cancers. Despite recent advances in medicine, mortality from colorectal cancer remains high, highlighting the need for improved therapies. Numerous studies have demonstrated increased activation of EGFR and its family members (EGFRs), IGF-1R as well as c-Src in colorectal cancer. The current study was undertaken to examine the effectiveness of combination therapy of dasatinib (BMS-354825; Bristol-Myers Squibb), a highly specific inhibitor of Src family kinases (SFK) and a nontoxic dietary agent; curcumin (diferuloylmethane), in colorectal cancer in in vitro and in vivo experimental models. For the latter, we utilized C57BL/6 APC(Min+/-) mice. Initial in vitro studies revealed synergistic interactions between the two agents. Additionally, we have observed that combination treatment causes a much greater inhibition of the following metastatic processes than either agent alone: (i) colony formation, (ii) invasion through extracellular matrix and (iii) tubule formation by endothelial cells. Dasatinib affects the cell adhesion phenotype of colon cancer HCT-116 cells whereas the combination therapy enhances this effect to a greater extent. Preclinical investigation revealed that the combination therapy to be highly effective causing an over 95% regression of intestinal adenomas in Apc(Min+/-) mice, which could be attributed to decreased proliferation and increased apoptosis. In conclusion, our data suggest that combination treatment of dasatinib and curcumin could be a potential therapeutic strategy for colorectal cancer.

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• Difluorinated-Curcumin (CDF): A Novel Curcumin Analog is a Potent Inhibitor of Colon Cancer Stem-Like Cells.

  Authors: Shailender Singh Kanwar, Yingjie Yu, Jyoti Nautiyal, Bhaumik B Patel, Subhash Padhye, Fazlul H Sarkar, Adhip P N Majumdar

  Pharmaceutical research.

  PURPOSE: Recurrence of colon cancer, which affects nearly 50% of patients treated by conventional therapeutics, is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-likePURPOSE: Recurrence of colon cancer, which affects nearly 50% of patients treated by conventional therapeutics, is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs). Therefore, development of therapeutic strategies for targeted elimination of CSCs would be a novel strategy. The current study examines whether diflourinated-curcumin (CDF), a novel analog of the dietary ingredient of curcumin, in combination with 5-fluorouracil and oxaliplatin (5-FU + Ox), the mainstay of colon cancer chemotherapeutic, would be effective in eliminating colon CSCs. METHODS: Multiple methodologies that include real-time RT-PCR, Western blot, MTT assay, caspase-3 activity, colonosphere formation, Hoechst-33342 dye exclusion and NF-κB-ELISA were used. RESULTS: We observed that CDF together with 5-FU + Ox were more potent than curcumin in reducing CD44 and CD166 in chemo-resistant colon cancer cells, accompanied by inhibition of growth, induction of apoptosis and disintegration of colonospheres. These changes were associated with down-regulation of the membrane transporter ABCG2 and attenuation of EGFR, IGF-1R, and NF-κB signaling consistent with inactivation of β-catenin, COX-2, c-Myc and Bcl-xL and activation of the pro-apoptotic Bax. CONCLUSIONS: Our results suggest that CDF together with the conventional chemotherapeutics could be an effective treatment strategy for preventing the emergence of chemo-resistant colon cancer cells by eliminating CSCs.

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• EGFR(s) in aging and carcinogenesis of the gastrointestinal tract.

  Authors: Jyoti Nautiyal, Shailender Singh Kanwar, Adhip P N Majumdar

  Current protein & peptide science. 11(6):436-50.

  Cells of the gastrointestinal (GI) mucosa are subject to a constant process of renewal which, in normal adults, reflects a balance between the rates of cell production and cell loss. DetailedCells of the gastrointestinal (GI) mucosa are subject to a constant process of renewal which, in normal adults, reflects a balance between the rates of cell production and cell loss. Detailed knowledge of these events is, therefore, essential for a better understanding of the normal aging processes as well as many GI diseases, particularly malignancy, that represent disorders of tissue growth. In general, many GI dysfunctions, including malignancy, increase with advancing age, and aging itself is associated with alterations in structural and functional integrity of the GI tract. Although the regulatory mechanisms for age-related increase in the incidence of GI-cancers are yet to be fully delineated, recent evidence suggests a role for epidermal growth family receptors and its family members {referred to as EGFR(s)} in the development and progression of carcinogenesis during aging. The present communication discusses the involvement of EGFR(s) in regulating events of GI cancers during advancing age and summarizes the current available therapeutics targeting these receptors. The current review also describes the effectiveness of ErbB inhibitors as well as combination therapies. Additionally, the involvement of GI stem cells in the development of the age-related rise in GI cancers is emphasized.

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• ErbB-inhibitory protein: a modified ectodomain of epidermal growth factor receptor synergizes with dasatinib to inhibit growth of breast cancer cells.

  Authors: Jyoti Nautiyal, Yingjie Yu, Amro Aboukameel, Shailender S Kanwar, Jayanta K Das, Jianhua Du, Bhaumik B Patel, Fazlul H Sarkar, Arun K Rishi, Ramzi M Mohammad, Adhip P N Majumdar

  Molecular cancer therapeutics. 9(6):1503-14.

  Many solid tumors, including breast cancer, show increased activation of several growth factor receptors, specifically epidermal growth factor receptor (EGFR) and its family members as well as c-Src,Many solid tumors, including breast cancer, show increased activation of several growth factor receptors, specifically epidermal growth factor receptor (EGFR) and its family members as well as c-Src, a nonreceptor tyrosine kinase that promotes proliferation, inhibits apoptosis, and induces metastasis. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for triple-negative breast cancer. To test our hypothesis, we used a c-Src-specific inhibitor dasatinib (BMS-354825; Bristol-Myers Squibb) and our newly developed ErbB-inhibitory protein (EBIP), a potential pan-ErbB inhibitor, in breast cancer cells. EBIP is composed of 1 to 448 amino acids of the ectodomain of human EGFR to which the 30-amino acid epitope (known as "U" region) of rat EGFR-related protein is fused at the COOH-terminal end. The combination of dasatinib and EBIP was found to be highly effective in inhibiting the growth of four different breast cancer cells (MDA-MB-468, SKBr-3, MDA-MB-453, and MDA-MB-231) that express different levels of EGFRs. In EGFR-overexpressing MDA-MB-468 cells, the combination, but not monotherapy, markedly stimulated apoptosis mediated by caspase-9 and caspase-8 and attenuated activation of EGFR and Src as well as tyrosine kinase activity. EBIP also inhibited heregulin-induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells. The combination therapy was highly effective in suppressing tumor growth ( approximately 90% inhibition) in MDA-MB-468-derived xenografts in severe combined immunodeficient mice. The latter could be attributed to induction of apoptosis. We conclude that combining dasatinib and EBIP could be an effective therapeutic strategy for breast cancer by targeting EGFRs and Src signaling.

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• EGFR(s) Inhibitors in the Treatment of Gastro-Intestinal Cancers: What's New?

  Authors: Shailender Singh Kanwar, Jyoti Nautiyal, Adhip P N Majumdar

  Current drug targets.

  In the past 10 to 15 years, a considerable progress has been made in the treatment of gastrointestinal (GI) related malignancies, as number of agents expanded from only one in 1995 to seven in 2006.In the past 10 to 15 years, a considerable progress has been made in the treatment of gastrointestinal (GI) related malignancies, as number of agents expanded from only one in 1995 to seven in 2006. Current review describes the recent role of targeted therapies, specifically EGFR inhibitors in the treatment of GI cancers. Importance of dietary agents in the treatment and prevention of GI cancers is also reviewed.

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• The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres.

  Authors: Shailender S Kanwar, Yingjie Yu, Jyoti Nautiyal, Bhaumik B Patel, Adhip P N Majumdar

  Molecular cancer. 9:212.

  Recent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells termed cancer stem cells (CSCs) which areRecent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells termed cancer stem cells (CSCs) which are thought to be responsible for recurrence of cancer. One of the characteristics of CSCs is their ability to form floating spheroids under anchorage-independent conditions in a serum-free defined media. The current investigation was undertaken to examine the role of Wnt/beta-catenin pathway in regulating the growth and maintenance of colonospheres. Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant), HCT-116 (p53 null; K-ras mutant) and HT-29 (p53 mutant) were used. Colonospheres formed in vitro exhibited higher expression of colon CSCs markers LGR5, CD44, CD166 and Musashi-1 along with putative CSC marker EpCAM, compared to the corresponding parental cancer cells and also exhibit the ability to form spheroids under extreme limiting dilution, indicating the predominance of CSCs in colonospheres. Colonospheres formed by HCT-116 cells show over 80% of the cells to be CD44 positive, compared to <or= 1% in the corresponding parental cells. Additionally, colonospheres showed reduced membrane bound beta-catenin but had increased levels of total beta-catenin, cyclin-D1 and c-myc and down regulation of axin-1 and phosphorylated beta-catenin. Increased expression of beta-catenin was associated with a marked transcriptional activation of TCF/LEF. The latter was greatly decreased following down regulation of beta-catenin by the corresponding siRNA, leading to a marked reduction in CD44 positive cells as well as colonospheres formation. In contrast, upregulation of c-myc, a down-stream effector of TCF/LEF greatly augmented the formation of colonospheres. Our data suggest that colonospheres formed by colon cancer cell lines are highly enriched in CSCs and that Wnt/beta-catenin pathway plays a critical role in growth and maintenance of colonospheres.

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• The Wnt/β-catenin pathway regulates growth and maintenance of colonospheres

  Authors: Shailender Kanwar, Yingjie Yu, Jyoti Nautiyal, Bhaumik Patel, Adhip Majumdar

  Molecular Cancer.

  Abstract Background Recent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells termed cancer stem cellsAbstract Background Recent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells termed cancer stem cells (CSCs) which are thought to be responsible for recurrence of cancer. One of the characteristics of CSCs is their ability to form floating spheroids under anchorage-independent conditions in a serum-free defined media. The current investigation was undertaken to examine the role of Wnt/β-catenin pathway in regulating the growth and maintenance of colonospheres. Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant), HCT-116 (p53 null; K-ras mutant) and HT-29 (p53 mutant) were used. Results Colonospheres formed in vitro exhibited higher expression of colon CSCs markers LGR5, CD44, CD166 and Musashi-1 along with putative CSC marker EpCAM, compared to the corresponding parental cancer cells and also exhibit the ability to form spheroids under extreme limiting dilution, indicating the predominance of CSCs in colonospheres. Colonospheres formed by HCT-116 cells show over 80% of the cells to be CD44 positive, compared to ≤ 1% in the corresponding parental cells. Additionally, colonospheres showed reduced membrane bound β-catenin but had increased levels of total β-catenin, cyclin-D1 and c-myc and down regulation of axin-1 and phosphorylated β-catenin. Increased expression of β-catenin was associated with a marked transcriptional activation of TCF/LEF. The latter was greatly decreased following down regulation of β-catenin by the corresponding siRNA, leading to a marked reduction in CD44 positive cells as well as colonospheres formation. In contrast, upregulation of c-myc, a down-stream effector of TCF/LEF greatly augmented the formation of colonospheres. Conclusion Our data suggest that colonospheres formed by colon cancer cell lines are highly enriched in CSCs and that Wnt/β-catenin pathway plays a critical role in growth and maintenance of colonospheres.

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• Elimination of Colon Cancer Stem-Like Cells by the Combination of Curcumin and FOLFOX.

  Authors: Yingjie Yu, Shailender S Kanwar, Bhaumik B Patel, Jyoti Nautiyal, Fazlul H Sarkar, Adhip Pn Majumdar

  Translational oncology. 2(4):321-8.

  5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics but with limited success. This could partly be due to the enrichment of cancer stem5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics but with limited success. This could partly be due to the enrichment of cancer stem cells (CSCs) that are resistant to conventional chemotherapy. Therefore, validation of a nontoxic agent that can either cause reversal of chemoresistance or promote the killing of CSCs would be highly desirable. The current study examines whether curcumin, the major active ingredient of turmeric, either alone or together with FOLFOX, would be an effective strategy to eliminate colon CSCs. Exposure of colon cancer HCT-116 or HT-29 cells to FOLFOX that inhibited their growth led to the enrichment of CSC phenotype as evidenced by increased proportion of CD133-, CD44-, and/or CD166-positive cells and epidermal growth factor receptor (EGFR) levels. Treatment of FOLFOX-surviving colon cancer cells with either curcumin alone or together with FOLFOX resulted in a marked reduction in CSCs, as evidenced by the decreased expression of CD44 and CD166 as well as EGFR and by their ability to form anchorage-dependent colonies. They also caused disintegration of colonospheres. Increased expression of EGFR in FOLFOX-surviving cells could be attributed to hypomethylation of the EGFR promoter, whereas an opposite phenomenon was observed when the FOLFOX-surviving cells were treated with curcumin and/or FOLFOX. These changes were accompanied by parallel alterations in the levels of DNA methyltransferase 1. In conclusion, our data suggest that curcumin by itself or together with the conventional chemotherapeutic could be an effective treatment strategy for preventing the emergence of chemoresistant colon cancer cells by reducing/eliminating CSCs.

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• Na(+)-stimulated Na+/H+ exchange and an unfavorable Ca2+ homeostasis initiate the cycloxygenase-2 inhibitors-induced apoptotic signals in colonic epithelial cells during the early stage of colon carcinogenesis.

  Authors: Shailender Singh Kanwar, Karnati R Roy, Bimla Nehru, Pallu Reddanna, Sankar Nath Sanyal

  Oncology research. 18(5-6):243-57.

  Evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cycloxygenase (COX) and production of the proinflammatory prostaglandin, PGE2, and thus prevent carcinogenesis in theEvidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cycloxygenase (COX) and production of the proinflammatory prostaglandin, PGE2, and thus prevent carcinogenesis in the colon. Indeed, one of the specific COX-2 inhibitors, celecoxib, had been accepted by the US FDA for the treatment of familial adenomatous polyposis. However, the molecular mechanism of such inhibition is not clear, although apoptosis appears to be the dominant antiproliferative end effect. The present study delineates the intracellular ionic milieu in the colonocytes that could generate strong apoptotic signals where DMH-induced carcinogenesis was studied in the initiation stage in rats and its regression with the COX inhibitors. While DMH treatment produced a significant elevation in the Na+/H+ exchanger activity and resultant proton efflux, this was reversed by the NSAIDs, particularly so with celecoxib and etoricoxib compared to aspirin. Similarly, the intracellular pH was changed, with more alkalosis noted in DMH, which was reversed by NSAIDs. Also, an intracellular Ca2+ build up was noted by Fura 2 AM, which was also supported by a reduced Ca2+ ATPase and an enhanced inward movement of Ca2+. Further, mitochondrial dysfunction-related cyt C release, increased DNA ladder formation, activation of caspase-3, and cleavage product of poly (ADP-ribose) polymerase (PARP) were not seen in DMH but well noted in NSAIDs. Our results indicate that NSAIDs can induce apoptosis through a change in the colonic Na+/H+ exchange, intracellular pH, and an unfavorable Ca2+ homeostasis.

• ROLE OF CERTAIN NON STEROIDAL ANTI-INFLAMMATORY DRUGS IN THE CHEMOPREVENTION OF 1,2-DIMETHYL HYDRAZINE INDUCED COLON CARCINOGENESIS IN RAT MODEL

  Authors: Shailender Singh Kanwar

  Degree: DOCTOR OF PHILOSOPHY

  Supervisor: Dr. Sankar Nath Sanyal (Professor)

• Induction of apoptosis by ‘COXIBs’ involve intracellular pH and calcium-ion concentration changes during experimental colon carcinogenesis

  Authors: Shailender Singh Kanwar, Kim Vaiphei, Bimla Nehru, Sankar Nath Sanyal

  IXth World Conference on Clinical Pharmacology and Therapeutics;

• Cyclooxygenase-2 inhibition by etoricoxib modulates plasma membrane fluidity in rat colon.

  Authors: Nancy Behal, Shailender Singh Kanwar, Jasmeet Kaur, Sankar Nath Sanyal

  Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 27(4):295-302.

  The present study was designed to investigate the effects of a selective cycloogenase-2 (COX-2) inhibitor, etoricoxib, on the membrane-specific enzymes, lipid composition, and changes in fluidityThe present study was designed to investigate the effects of a selective cycloogenase-2 (COX-2) inhibitor, etoricoxib, on the membrane-specific enzymes, lipid composition, and changes in fluidity parameters of rat colonic plasma membrane. Two doses of the drug were used, one within its therapeutic anti-inflammatory range as based on the ED50 value in rats (Eto-1), while the other at 10 times higher dose relating to the toxicity studies (Eto-2), which have not been reported so far. The activity of the membrane alkaline phosphatase was found to be increased after treatment with both the doses of etoricoxib as compared to the control. The total lipid and the cholesterol content showed a decrease while an increase in ganglioside sialic acid content was noted. Phospholipid content and the cholesterol-phospholipid molar ratio showed no change in either of the treatment groups. Fluorescence polarization studies with diphenylhexatriene showed that membrane fluidity was least altered in the isolated brush border membrane from colon or in the liposomes prepared from the membrane lipid extracts. Also, the translational diffusion studied with pyrene showed that the fluidity parameter was decreased as measured by the excimer formation. It is concluded that etoricoxib, a new generation COX-2 inhibitor (called the coxibs), appeared to be a safe nonsteroidal anti-inflammatory drug (NSAID) in the colonic membranes.

• Antioxidative effects of nonsteroidal anti-inflammatory drugs during the initiation stages of experimental colon carcinogenesis in rats.

  Authors: Shailender S Kanwar, Kim Vaiphei, Bimla Nehru, Sankar N Sanyal

  Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 27(2):89-100.

  The role of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied on the antioxidant defense system and nitric oxide-derived damage in a 1,2-dimethylhydrazine (DMH)-induced rat colonThe role of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied on the antioxidant defense system and nitric oxide-derived damage in a 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Early precancerous lesions were established in the proximal and distal regions of the colon by morphological and histopathological examinations that were greatly regressed by the simultaneous treatment of the three NSAIDs, such as aspirin, celecoxib, and etoricoxib, along with the procarcinogen DMH. The intestinal brush border membrane (BBM) was isolated from the two regions and the colon-specific marker enzyme cysteine-sensitive alkaline phosphatase was assayed, which showed considerable elevation by DMH but reverted back to normal level by all the three NSAIDs. DMH also caused a higher level of lipid peroxidation as measured by malonyldialdehyde production, which was also found to be corrected by the NSAIDs, in both the region of the colonic tissue. The antioxidant activities were further established by a higher level of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase in the NSAID treatment as compared to the DMH. The nonenzyme tripeptide, glutathione content was also recovered similarly as an antioxidant defense mechanism. To elucidate whether nitric oxide (NO) also plays an important role in the pathophysiology of colon cancer, the NO and citrulline levels were measured. The results show that the NO was lowered in DMH treatment and elevated by the administration of the NSAIDs while the citrulline level could not be recovered back. The findings of the present investigation indicate the chemopreventive modalities of the NSAIDs, particularly the COX-2 inhibitors.

• The Effect of Etoricoxib, a Cyclooxygenase-2-Specific Inhibitor, on the 1,2-Dimethylhydrazine-Administered Rat Intestinal Membrane Structure and Function.

  Authors: Neha Mittal, Shailender Singh Kanwar, Sankar Nath Sanyal

  Toxicology mechanisms and methods. 18(1):53-62.

  ABSTRACT To gain insight into the chemopreventive effects of etoricoxib, which is a selective inhibitor of cycloxygenase-2, a study was carried out in the procarcinogen 1,2-dimethylhydrazine-treatedABSTRACT To gain insight into the chemopreventive effects of etoricoxib, which is a selective inhibitor of cycloxygenase-2, a study was carried out in the procarcinogen 1,2-dimethylhydrazine-treated rat intestine. The male Sprague Dawley rats were divided into three different groups. Group 1 served as control (vehicle treated). All animals in Group 2 were given a weekly subcutaneous injection of 1,2-dimethylhydrazine (DMH; 30 mg/kg body weight) for 6 weeks. Group 3 animals were given an additional oral dose of etoricoxib (6 mg/kg body weight) along with weekly DMH injections for 6 weeks. At the end of 6 weeks of treatments, the results indicated significant alterations in the biochemical parameters, membrane lipid composition, and membrane fluorescence studies of the intestine in the presence of DMH, which were recovered nearly to the control level and, therefore, may suggest the chemopreventive efficacy of etoricoxib against the experimental intestinal cancer in rats.

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• Modulation of intracellular pH and Ca2+ concentration in experimental colon cancer and chemoprevention

  Authors: Shailender Singh Kanwar, Kim Vaiphei, Bimla Nehru, Sankar Nath Sanyal

  National symposium on Biophysics, Biophysics in Medicine and Biology;

• Chemopreventive effects of non steroidal anti-inflammatory drugs on 1, 2-dimethylhydrazine-induced colon carcinogenesis in rats

  Authors: Shailender Singh Kanwar, Kim Vaiphei, Bimla Nehru, Sankar Nath Sanyal

  Toxicology Mechanisms Methods. 17:197-204.

  The anticancer efficacy of two different classes of NSAIDs, the nonspecific cyclooxygenase (COX) inhibitor aspirin and the specific COX-2 inhibitor celecoxib, was examined at their therapeuticThe anticancer efficacy of two different classes of NSAIDs, the nonspecific cyclooxygenase (COX) inhibitor aspirin and the specific COX-2 inhibitor celecoxib, was examined at their therapeutic anti-inflammatory doses during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in a rat model. Eight to 10-week-old male rats of Sprague strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, groups 2, 3, and 4 were administered freshly prepared DMH in 1 mM EDTA saline (pH 7.0) (30 mg/kg body weight/week, subcutaneously). Groups 3 and 4 were also given a daily treatment of aspirin (60 mg/kg body weight, orally) and celecoxib (6 mg/kg body weight, orally), respectively, both prepared in carboxy-methyl cellulose. Animals were sacrificed at the end of 12 weeks and colons from different groups were subjected to macroscopic and histopathological studies, enzymatic activities of superoxide dismutase (SOD) and catalase (CAT), and determination of lipid peroxide level. The maximum number of raised mucosal lesions in proximal, middle, and distal regions of the colon was found in the DMH group alone, and the lowest number was found in the celecoxib-treated DMH group. Histological studies also showed the highest occurrence of dysplastic aberrant crypt foci (ACF) associated with enlarged lymphoid follicles in all the three portions of colon (i.e., proximal, middle, and distal). The aspirin-administered DMH group had lesser ACF in the proximal and middle portions and no ACF in the distal region. The celecoxib-administered DMH group showed no ACF in the middle region of the rat colon. DMH treatment induced lipid peroxidation and inhibited the activities of SOD and CAT. Both the aspirin- and celecoxib-treated DMH groups showed a marked lowering of the lipid peroxide level along with a significant enhancement of CAT activity when compared with the DMH-treated group. The results show that celecoxib was found to be more effective in reducing the ACF occurrence and aggregates of lymphoid tissue than the nonselective COX inhibitor aspirin, and suggests a possible chemoprevention modality in colon cancer. This may have important implications as COX-2 selective drugs at anti-inflammatory doses are better tolerated clinically than standard NSAIDs, thus making them potentially better chemopreventive agents in colon cancer.