Program Official

Principal Investigator

Shrikant
Anant
Awardee Organization

University Of Kansas Medical Center
United States

Fiscal Year
2018
Activity Code
R01
Project End Date

Bitter Melon Component and Colon Cancer Prevention

Despite the best screening efforts to identify and remove colon polyps, colon cancer remains a leading cause of cancer related morbidity and mortality, both in the US and around the world. Also, current therapeutics while good in removing most cancer cells are not adequate because they leave some cells behind. This is because these cells can reemerge and develop a fresh tumor, which in many cases can manifest in a different organ due to metastasis. The advantage of using natural products that originate from fruits and vegetables over synthetic agents for preventing cancer is that they promote human health without recognizable side effects. In this regard, we have recently shown that bitter melon extracts (BME) inhibit the growth of DCLK1+ cells. We have now discovered that charantin, an active ingredient in the extracts is a potent inhibitor of colon cancer growth. The goal of the current project is to further characterize charantin and generate preclinical data as a dietary agent for the prevention of colon cancer. In preliminary studies, we have determined that charantin inhibits DCLK1 kinase activity and that of a related kinase CAMKIIa but not that of CAMKIIb and CAMKIV. Furthermore, charantin inhibits DCLK1 induced phosphorylation of AKT1/PKB. AKT1 is a serine-threonine protein kinase that is catalytically inactive until it is phosphorylated at two critical sites, Thr308 and Ser473. Various agents such as growth factors, and cytokines can rapidly activate the protein through the actions of phosphatidylinositol 3-kinase (PI3K). Upon activation, AKT1 induces phosphorylation of GSK-3b and also inhibits JNK activation. We have determined that charantin suppresses AKT1 activation and induces JNK. Moreover, JNK induces β-catenin phosphorylation, which in turn is subjected to b-TRCP independent, SIAH1- dependent ubiquitin-proteasome degradation pathway. We have also determined that charantin inhibits the growth of colon cancer cells in a novel culture method termed "Tumor in a Dish" (TiD). In this system, cells are grown in a three dimensional matrix that contains normal lung cells including normal epithelial cells, fibroblasts and endothelial cells. The model creates a near-in vivo tumor microenvironment including cell-cell contact, 3D- architecture, and the influence of different cell types. The observed selective killing of cancer cells in this system suggests that the compounds are highly specific and have good potency. Based on these preliminary results, we propose to further develop charantin as a dietary prevention agent and move it towards the clinic. In aim 1, we propose to determine the role of PI3 kinase in charantin effect on DCLK1-mediated AKT1 activation. In Aim 2, we propose to determine whether charantin affects AKT-mediated β-catenin activation. Finally, in Aim 3, we will determine whether charantin induces JNK1 kinase and SIAH1 to induce β-catenin degradation. We will determine the effect of the compound on DCLK1 expression, and on Akt phosphorylation, and β-catenin degradation. These studies will also aid in understanding a non-canonical pathway to suppress β-catenin signaling and identify novel biomarkers for the future clinical studies.

Publications

  • Dandawate P, Ghosh C, Palaniyandi K, Paul S, Rawal S, Pradhan R, Sayed AAA, Choudhury S, Standing D, Subramaniam D, Padhye SB, Gunewardena S, Thomas SM, Neil MO, Tawfik O, Welch DR, Jensen RA, Maliski S, Weir S, Iwakuma T, Anant S, Dhar A. The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice. Gastroenterology. 2019 Dec;157(6):1646-1659.e11. Epub 2019 Aug 20. PMID: 31442435
  • Schmitt F, Subramaniam D, Anant S, Padhye S, Begemann G, Schobert R, Biersack B. Halogenated Bis(methoxybenzylidene)-4-piperidone Curcuminoids with Improved Anticancer Activity. ChemMedChem. 2018 Jun 6;13(11):1115-1123. Epub 2018 Apr 23. PMID: 29570947
  • Ahmed I, Roy BC, Subramaniam D, Ganie SA, Kwatra D, Dixon D, Anant S, Zargar MA, Umar S. An ornamental plant targets epigenetic signaling to block cancer stem cell-driven colon carcinogenesis. Carcinogenesis. 2016 Apr;37(4):385-96. Epub 2016 Jan 19. PMID: 26785732
  • Krishnamachary B, Subramaniam D, Dandawate P, Ponnurangam S, Srinivasan P, Ramamoorthy P, Umar S, Thomas SM, Dhar A, Septer S, Weir SJ, Attard T, Anant S. Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone. Oncotarget. 2019 Sep 24;10(54):5576-5591. doi: 10.18632/oncotarget.27159. eCollection 2019 Sep 24. PMID: 31608135
  • Subramaniam D, Angulo P, Ponnurangam S, Dandawate P, Ramamoorthy P, Srinivasan P, Iwakuma T, Weir SJ, Chastain K, Anant S. Suppressing STAT5 signaling affects osteosarcoma growth and stemness. Cell death & disease. 2020 Feb 24;11(2):149. PMID: 32094348
  • Paul S, Ramalingam S, Subramaniam D, Baranda J, Anant S, Dhar A. Histone Demethylases in Colon Cancer. Current colorectal cancer reports. 2014 Dec 1;10(4):417-424. PMID: 25574158
  • Liu W, Woolbright BL, Pirani K, Didde R, Abbott E, Kaushik G, Martin P, Hamilton-Reeves J, Taylor JA 3rd, Holzbeierlein JM, Anant S, Lee EK. Tumor M2-PK: A novel urine marker of bladder cancer. PloS one. 2019 Jun 27;14(6):e0218737. doi: 10.1371/journal.pone.0218737. eCollection 2019. PMID: 31246990
  • Blanco FF, Preet R, Aguado A, Vishwakarma V, Stevens LE, Vyas A, Padhye S, Xu L, Weir SJ, Anant S, Meisner-Kober N, Brody JR, Dixon DA. Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis. Oncotarget. 2016 Nov 8;7(45):74043-74058. PMID: 27677075
  • Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Seminars in cancer biology. 2016 Oct;40-41:192-208. Epub 2016 Sep 5. PMID: 27609747
  • Dandawate P, Kaushik G, Ghosh C, Standing D, Ali Sayed AA, Choudhury S, Subramaniam D, Manzardo A, Banerjee T, Santra S, Ramamoorthy P, Butler M, Padhye SB, Baranda J, Kasi A, Sun W, Tawfik O, Coppola D, Malafa M, Umar S, Soares MJ, Saha S, Weir SJ, Dhar A, Jensen RA, Thomas SM, Anant S. Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice. Gastroenterology. 2020 Apr;158(5):1433-1449.e27. Epub 2019 Nov 29. PMID: 31786131
  • Mali AV, Padhye SB, Anant S, Hegde MV, Kadam SS. Anticancer and antimetastatic potential of enterolactone: Clinical, preclinical and mechanistic perspectives. European journal of pharmacology. 2019 Jun 5;852:107-124. Epub 2019 Feb 14. PMID: 30771348
  • Vekaria PH, Kumar A, Subramaniam D, Dunavin N, Vallurupalli A, Schoenen F, Ganguly S, Anant S, McGuirk JP, Jensen RA, Rao R. Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells. Leukemia. 2019 Jul;33(7):1675-1686. Epub 2019 Jan 21. PMID: 30664664
  • Venugopal A, Subramaniam D, Balmaceda J, Roy B, Dixon DA, Umar S, Weir SJ, Anant S. RNA binding protein RBM3 increases β-catenin signaling to increase stem cell characteristics in colorectal cancer cells. Molecular carcinogenesis. 2016 Nov;55(11):1503-1516. Epub 2015 Aug 31. PMID: 26331352
  • Spaw M, Anant S, Thomas SM. Stromal contributions to the carcinogenic process. Molecular carcinogenesis. 2017 Apr;56(4):1199-1213. Epub 2016 Nov 5. PMID: 27787930
  • Crooker K, Aliani R, Ananth M, Arnold L, Anant S, Thomas SM. A Review of Promising Natural Chemopreventive Agents for Head and Neck Cancer. Cancer prevention research (Philadelphia, Pa.). 2018 Aug;11(8):441-450. Epub 2018 Mar 30. PMID: 29602908
  • Roy BC, Ahmed I, Ramalingam S, Jala V, Haribabu B, Ramamoorthy P, Ashcraft J, Valentino J, Anant S, Sampath V, Umar S. Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression. Oncotarget. 2019 Mar 22;10(24):2340-2354. doi: 10.18632/oncotarget.26684. eCollection 2019 Mar 22. PMID: 31040926
  • Kaushik G, Kwatra D, Subramaniam D, Jensen RA, Anant S, Mammen JM. Honokiol affects melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway. American journal of surgery. 2014 Dec;208(6):995-1002; discussion 1001-2. Epub 2014 Oct 2. PMID: 25450590
  • Ghosh C, Paul S, Dandawate P, Gunewardena SS, Subramaniam D, West C, Anant S, Dhar A. Super-enhancers: novel target for pancreatic ductal adenocarcinoma. Oncotarget. 2019 Feb 22;10(16):1554-1571. doi: 10.18632/oncotarget.26704. eCollection 2019 Feb 22. PMID: 30899425
  • Snyder V, Reed-Newman TC, Arnold L, Thomas SM, Anant S. Cancer Stem Cell Metabolism and Potential Therapeutic Targets. Frontiers in oncology. 2018 Jun 5;8:203. doi: 10.3389/fonc.2018.00203. eCollection 2018. PMID: 29922594
  • Dandawate PR, Subramaniam D, Padhye SB, Anant S. Bitter melon: a panacea for inflammation and cancer. Chinese journal of natural medicines. 2016 Feb;14(2):81-100. PMID: 26968675
  • New J, Subramaniam D, Ramalingam S, Enders J, Sayed AAA, Ponnurangam S, Standing D, Ramamoorthy P, O'Neil M, Dixon DA, Saha S, Umar S, Gunewardena S, Jensen RA, Thomas SM, Anant S. Pleotropic role of RNA binding protein CELF2 in autophagy induction. Molecular carcinogenesis. 2019 Aug;58(8):1400-1409. Epub 2019 Apr 24. PMID: 31020708
  • Ramamoorthy P, Thomas SM, Kaushik G, Subramaniam D, Chastain KM, Dhar A, Tawfik O, Kasi A, Sun W, Ramalingam S, Gunewardena S, Umar S, Mammen JM, Padhye SB, Weir SJ, Jensen RA, Sittampalam GS, Anant S. Metastatic Tumor-in-a-Dish, a Novel Multicellular Organoid to Study Lung Colonization and Predict Therapeutic Response. Cancer research. 2019 Apr 1;79(7):1681-1695. Epub 2019 Jan 23. PMID: 30674533
  • Angulo P, Kaushik G, Subramaniam D, Dandawate P, Neville K, Chastain K, Anant S. Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy. Journal of hematology & oncology. 2017 Jan 7;10(1):10. PMID: 28061797
  • Rangarajan P, Subramaniam D, Paul S, Kwatra D, Palaniyandi K, Islam S, Harihar S, Ramalingam S, Gutheil W, Putty S, Pradhan R, Padhye S, Welch DR, Anant S, Dhar A. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells. Oncotarget. 2015 Sep 29;6(29):27661-73. PMID: 26317547
  • Kumar D, New J, Vishwakarma V, Joshi R, Enders J, Lin F, Dasari S, Gutierrez WR, Leef G, Ponnurangam S, Chavan H, Ganaden L, Thornton MM, Dai H, Tawfik O, Straub J, Shnayder Y, Kakarala K, Tsue TT, Girod DA, Van Houten B, Anant S, Krishnamurthy P, Thomas SM. Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression. Cancer research. 2018 Jul 15;78(14):3769-3782. Epub 2018 May 16. PMID: 29769197
  • Linder B, Köhler LHF, Reisbeck L, Menger D, Subramaniam D, Herold-Mende C, Anant S, Schobert R, Biersack B, Kögel D. A New Pentafluorothio-Substituted Curcuminoid with Superior Antitumor Activity. Biomolecules. 2021 Jun 25;11. (7). PMID: 34202286
  • Weir SJ, Wood R, Schorno K, Brinker AE, Ramamoorthy P, Heppert K, Rajewski L, Tanol M, Ham T, McKenna MJ, McCulloch W, Dalton M, Reed GA, Jensen RA, Baltezor MJ, Anant S, Taylor JA 3rd. Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs. The Journal of pharmacology and experimental therapeutics. 2019 Aug;370(2):148-159. Epub 2019 May 21. PMID: 31113837
  • Ponnurangam S, Dandawate PR, Dhar A, Tawfik OW, Parab RR, Mishra PD, Ranadive P, Sharma R, Mahajan G, Umar S, Weir SJ, Sugumar A, Jensen RA, Padhye SB, Balakrishnan A, Anant S, Subramaniam D. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget. 2016 Jan 19;7(3):3217-32. PMID: 26673007
  • Ramalingam S, Subramaniam D, Anant S. Manipulating miRNA Expression: A Novel Approach for Colon Cancer Prevention and Chemotherapy. Current pharmacology reports. 2015 Jun 1;1(3):141-153. PMID: 26029495
  • Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Current medicinal chemistry. 2018;25(22):2585-2594. PMID: 28137215