Principal Investigator

Chengguo
Xing
Awardee Organization

University Of Florida
United States

Fiscal Year
2019
Activity Code
R01
Project End Date

Dihydromethysticin (DHM) for Lung Cancer Chemoprevention

Lung cancer causes ~160,000 deaths annually in the U.S. and prevention will be crucial to win the war on this deadliest cancer. Since DNA modification by tobacco carcinogens is one major driver for lung cancer initiation, blocking DNA adduct formation (the root cause) is a plausible strategy. This proposal focuses on the preclinical studies of dihydromethysticin (DHM) as a novel and highly efficacious chemopreventive agent that inhibits lung tumor initiation via preventing tobacco carcinogen-induced DNA modification. Preliminary data demonstrate that DHM (given during carcinogen exposure period at a dose of 50 ppm in diet) completely blocked NNK-induced lung tumor formation in A/J mice. A natural analog, dihydrokavain (DHK), was completely inactive even at 500 ppm in diet. Such a sharp in vivo difference suggests a crucial role of methylenedioxy functional group for specific targeting by DHM. DHM selectively reduced NNAL (the active metabolite of NNK)-induced DNA adducts in the lung tissues. DHM also reduced NNK-derived DNA adducts in F344 rats, indicating its cross-species anti-initiation potential. Based on the reported activity of DHM in activating aryl hydrocarbon receptor (AHR) and our own data of DHM in increasing glucuronidated NNAL in mouse urine, we propose that DHM activates detoxification pathways as the primary mechanism of action. With respect to safety, 17-week dietary exposure of DHM to A/J mice caused no adverse effects at 500 ppm, affording a wide safety margin as a lung cancer chemopreventive agent for long-term use. Our central hypothesis is that DHM effectively prevents tobacco carcinogen-induced lung tumorigenesis, at least in major part, by enhancing carcinogen detoxification potentially via activating AHR leading to a reduction in oncogenic DNA adducts in the target lung tissues. This hypothesis will be tested by accomplishing the following aims: Aim 1 To elucidate the structural determinant(s) of DHM (i.e., intact DHM or its metabolite) for its exceptional in vivo inhibitory activities against NNK-induced DNA adduct formation and lung tumor initiation. Data will also inform the in vivo active form of DHM. Aim 2 To investigate enhanced detoxification as a key mechanism of DHM to inhibit NNK-induced DNA adduct formation and lung tumor initiation. Data will also inform its potential to protect against other tobacco carcinogens and identify surrogate biomarkers for future translational studies. Aim 3 To evaluate the efficacy of DHM against NNK-induced lung tumorigenesis in F344 rats and BaP-induced lung tumorigenesis in A/J mice. Data will inform its cross-species applicability and carcinogen specificity. If the results support our hypothesis, DHM will be well positioned for Good Laboratory Practice (GLP)-based toxicology in higher mammals in preparation for an IND application for human translation studies. The mechanistic knowledge will not only identify surrogate biomarkers critical for translation, but also advance our basic understanding about NNAL metabolism and carcinogenesis.

Publications

  • Hati S, Hu Q, Huo Z, Lu J, Xing C. In vivo Structure-Activity Relationship of Dihydromethysticin in Reducing Nicotine-Derived Nitrosamine Ketone (NNK)-Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice. ChemMedChem. 2022 Apr 5;17(7):e202100727. Epub 2022 Mar 4. PMID: 35064644
  • Martin AC, Johnston E, Xing C, Hegeman AD. Measuring the chemical and cytotoxic variability of commercially available kava (Piper methysticum G. Forster). PloS one. 2014 Nov 3;9(11):e111572. doi: 10.1371/journal.pone.0111572. eCollection 2014. PMID: 25365244
  • Wang Y, Fujioka N, Xing C. Quantitative profiling of cortisol metabolites in human urine by high-resolution accurate-mass MS. Bioanalysis. 2018 Dec;10(24):2015-2026. Epub 2018 Nov 6. PMID: 30412681
  • Cong H, Zhao X, Castle BT, Pomeroy EJ, Zhou B, Lee J, Wang Y, Bian T, Miao Z, Zhang W, Sham YY, Odde DJ, Eckfeldt CE, Xing C, Zhuang C. An Indole-Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules. Molecular pharmaceutics. 2018 Sep 4;15(9):3892-3900. Epub 2018 Aug 9. PMID: 30048137
  • Wang Y, Narayanapillai S, Hu Q, Fujioka N, Xing C. Contribution of Tobacco Use and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone to Three Methyl DNA Adducts in Urine. Chemical research in toxicology. 2018 Sep 17;31(9):836-838. Epub 2018 Aug 24. PMID: 30136842
  • Bian T, Chandagirikoppal Vijendra K, Wang Y, Meacham A, Hati S, Cogle CR, Sun H, Xing C. Exploring the Structure-Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug-Resistant Cancer Cells. Journal of medicinal chemistry. 2018 Aug 9;61(15):6892-6903. Epub 2018 Jul 25. PMID: 29995404
  • Zhuang C, Wu Z, Xing C, Miao Z. Small molecules inhibiting Keap1-Nrf2 protein-protein interactions: a novel approach to activate Nrf2 function. MedChemComm. 2016 Nov 17;8(2):286-294. doi: 10.1039/c6md00500d. eCollection 2017 Feb 1. PMID: 30108745
  • Wang Y, Eans SO, Stacy HM, Narayanapillai SC, Sharma A, Fujioka N, Haddad L, McLaughlin J, Avery BA, Xing C. A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications. PloS one. 2018 May 24;13(5):e0197940. doi: 10.1371/journal.pone.0197940. eCollection 2018. PMID: 29795658
  • Bian T, Wang Y, Botello JF, Hu Q, Jiang Y, Zingone A, Ding H, Wu Y, Zahra Aly F, Salloum RG, Warren G, Huo Z, Ryan BM, Jin L, Xing C. LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner. Oncogene. 2022 Aug;41(33):4042-4054. Epub 2022 Jul 14. PMID: 35835853
  • Narayanapillai SC, Lin SH, Leitzman P, Upadhyaya P, Baglole CJ, Xing C. Dihydromethysticin (DHM) Blocks Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Induced O6-Methylguanine in a Manner Independent of the Aryl Hydrocarbon Receptor (AhR) Pathway in C57BL/6 Female Mice. Chemical research in toxicology. 2016 Nov 21;29(11):1828-1834. Epub 2016 Oct 21. PMID: 27728767
  • Bian T, Ding H, Wang Y, Hu Q, Chen S, Fujioka N, Aly FZ, Lu J, Huo Z, Xing C. Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung carcinogenesis. Carcinogenesis. 2022 Aug 30;43(7):659-670. PMID: 35353881
  • Wang Y, Narayanapillai SC, Tessier KM, Strayer LG, Upadhyaya P, Hu Q, Kingston R, Salloum RG, Lu J, Hecht SS, Hatsukami DK, Fujioka N, Xing C. The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers. Cancer prevention research (Philadelphia, Pa.). 2020 May;13(5):483-492. Epub 2020 Feb 26. PMID: 32102948
  • Cong H, Xu L, Wu Y, Qu Z, Bian T, Zhang W, Xing C, Zhuang C. Inhibitor of Apoptosis Protein (IAP) Antagonists in Anticancer Agent Discovery: Current Status and Perspectives. Journal of medicinal chemistry. 2019 Jun 27;62(12):5750-5772. Epub 2019 Feb 1. PMID: 30676015
  • Wang Y, Narayanapillai SC, Hu Q, Fujioka N, Xing C. Detection and quantification of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) from smoker albumin and its potential as a surrogate biomarker of tobacco-specific nitrosamines exposure and bioactivation. Toxicology letters. 2019 Sep 1;311:11-16. Epub 2019 Apr 23. PMID: 31026483
  • Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chemical reviews. 2017 Jun 28;117(12):7762-7810. Epub 2017 May 10. PMID: 28488435
  • Hu Q, Corral P, Narayanapillai SC, Leitzman P, Upadhyaya P, O'Sullivan MG, Hecht SS, Lu J, Xing C. Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice. Chemical research in toxicology. 2020 Jul 20;33(7):1980-1988. Epub 2020 Jun 11. PMID: 32476407
  • Narayanapillai SC, Leitzman P, O'Sullivan MG, Xing C. Flavokawains a and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chemical research in toxicology. 2014 Oct 20;27(10):1871-6. Epub 2014 Sep 12. PMID: 25185080
  • Tang SN, Zhang J, Jiang P, Datta P, Leitzman P, O'Sullivan MG, Jiang C, Xing C, Lü J. Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone-rich Kava fraction. Molecular carcinogenesis. 2016 Dec;55(12):2291-2303. Epub 2016 Feb 3. PMID: 26840761
  • Narayanapillai SC, Balbo S, Leitzman P, Grill AE, Upadhyaya P, Shaik AA, Zhou B, O'Sullivan MG, Peterson LA, Lu J, Hecht SS, Xing C. Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis. 2014 Oct;35(10):2365-72. Epub 2014 Jul 22. PMID: 25053626
  • Hu Q, Upadhyaya P, Hecht SS, Aly FZ, Huo Z, Xing C. Characterization of adductomic totality of NNK, (R)-NNAL and (S)-NNAL in A/J mice, and their correlations with distinct lung carcinogenicity. Carcinogenesis. 2022 Mar 24;43(2):170-181. PMID: 34919675
  • Narayanapillai SC, von Weymarn LB, Carmella SG, Leitzman P, Paladino J, Upadhyaya P, Hecht SS, Murphy SE, Xing C. Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification. Drug metabolism and disposition: the biological fate of chemicals. 2016 Mar;44(3):422-7. Epub 2016 Jan 7. PMID: 26744252
  • Puppala M, Narayanapillai SC, Leitzman P, Sun H, Upadhyaya P, O'Sullivan MG, Hecht SS, Xing C. Pilot in Vivo Structure-Activity Relationship of Dihydromethysticin in Blocking 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice. Journal of medicinal chemistry. 2017 Sep 28;60(18):7935-7940. Epub 2017 Sep 13. PMID: 28806079