Principal Investigator

Piyali
Dasgupta
Awardee Organization

Marshall University
United States

Fiscal Year
2021
Activity Code
R15
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Capsaicin and small cell lung cancer therapy

Capsaicin is the spicy, pungent ingredient of chili peppers. Conventionally, capsaicin is used as a pain-relieving agent in over-the-counter analgesic creams and lotions. Our research data showed for the first time that capsaicin triggered apoptosis in human small cell lung cancers (SCLCs). However, the development of capsaicin as a feasible anti-cancer drug is limited by its low biological half-life, unpleasant side effects including gut pain, hyperalgesia, stomach cramps and nausea. Biochemical studies have shown that capsaicin analogs containing long chain unsaturated fatty acids in its C-terminal region (called N-AVAMs) were non-pungent and possessed pain-relieving activity. Subsequently, we examined the anti-tumor activity of selected N-AVAM capsaicinoids. We observed that the non-pungent N-AVAM capsaicin analog arvanil displayed greater proapoptotic activity relative to capsaicin in human SCLCs. However, arvanil is a viscous liquid with poor solubility properties. Based on the structural motifs of arvanil, the present R15 renewal application proposes structureactivity relationship (SAR) studies to identify capsaicin analogs with improved bioavailability properties and antitumor activity and in human SCLCs. Furthermore, arvanil sensitized platinum-resistant human SCLCs to irinotecan-induced apoptosis. The chemosensitization activity of arvanil was greater than capsaicin in human SCLCs. Using these observations as proof-of-concept, the current renewal application will test the chemosensitization ability of a panel of non-pungent N-AVAM capsaicin analogs. The central hypothesis of our renewal application is that the SAR studies will lead to the identification of capsaicinoids which, will display robust anti-tumor activity as single agents and in combination with irinotecan in vivo. In addition, we aim to investigate the bioavailability of these N-AVAM capsaicin compounds in mice models. An innovative feature of our grant application is that we aim to test the anti-tumor activity and chemosensitization activity of these capsaicin analogs in PDX models of human SCLCs. The experimental models outlined in our proposal provide meaningful research experiences for undergraduate and graduate students. The results of our studies will foster the hope of novel therapies in classical and platinum-resistant SCLCs.

Publications

  • Hurley JD, Akers AT, Friedman JR, Nolan NA, Brown KC, Dasgupta P. Non-pungent long chain capsaicin-analogs arvanil and olvanil display better anti-invasive activity than capsaicin in human small cell lung cancers. Cell adhesion & migration. 2017 Jan 2;11(1):80-97. Epub 2016 May 19. PMID: 27196129
  • Lau JK, Brown KC, Dom AM, Witte TR, Thornhill BA, Crabtree CM, Perry HE, Brown JM, Ball JG, Creel RG, Damron CL, Rollyson WD, Stevenson CD, Hardman WE, Valentovic MA, Carpenter AB, Dasgupta P. Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway. Apoptosis : an international journal on programmed cell death. 2014 Aug;19(8):1190-201. PMID: 24878626
  • Friedman JR, Richbart SD, Merritt JC, Brown KC, Nolan NA, Akers AT, Lau JK, Robateau ZR, Miles SL, Dasgupta P. Acetylcholine signaling system in progression of lung cancers. Pharmacology & therapeutics. 2019 Feb;194:222-254. Epub 2018 Oct 3. PMID: 30291908
  • Lau JK, Brown KC, Dasgupta P. Measurement of Acetylcholine from Cell Lines. Bio-protocol. 2013;3. (24). Epub 2013 Dec 20. PMID: 27390758
  • Merritt JC, Richbart SD, Moles EG, Cox AJ, Brown KC, Miles SL, Finch PT, Hess JA, Tirona MT, Valentovic MA, Dasgupta P. Anti-cancer activity of sustained release capsaicin formulations. Pharmacology & therapeutics. 2022 Oct;238:108177. Epub 2022 Mar 26. PMID: 35351463
  • Friedman JR, Nolan NA, Brown KC, Miles SL, Akers AT, Colclough KW, Seidler JM, Rimoldi JM, Valentovic MA, Dasgupta P. Anticancer Activity of Natural and Synthetic Capsaicin Analogs. The Journal of pharmacology and experimental therapeutics. 2018 Mar;364(3):462-473. Epub 2017 Dec 15. PMID: 29246887
  • Friedman JR, Richbart SD, Merritt JC, Brown KC, Denning KL, Tirona MT, Valentovic MA, Miles SL, Dasgupta P. Capsaicinoids: Multiple effects on angiogenesis, invasion and metastasis in human cancers. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019 Oct;118:109317. Epub 2019 Aug 9. PMID: 31404777
  • Friedman JR, Perry HE, Brown KC, Gao Y, Lin J, Stevenson CD, Hurley JD, Nolan NA, Akers AT, Chen YC, Denning KL, Brown LG, Dasgupta P. Capsaicin synergizes with camptothecin to induce increased apoptosis in human small cell lung cancers via the calpain pathway. Biochemical pharmacology. 2017 Apr 1;129:54-66. Epub 2017 Jan 16. PMID: 28104436
  • Brown KC, Perry HE, Lau JK, Jones DV, Pulliam JF, Thornhill BA, Crabtree CM, Luo H, Chen YC, Dasgupta P. Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway. The Journal of biological chemistry. 2013 Nov 15;288(46):33049-59. Epub 2013 Oct 2. PMID: 24089524
  • Lau JK, Brown KC, Thornhill BA, Crabtree CM, Dom AM, Witte TR, Hardman WE, McNees CA, Stover CA, Carpenter AB, Luo H, Chen YC, Shiflett BS, Dasgupta P. Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma. Cancer research. 2013 Feb 15;73(4):1328-39. Epub 2012 Dec 7. PMID: 23222296
  • Brown KC, Modi KJ, Light RS, Cox AJ, Long TE, Gadepalli RS, Rimoldi JM, Miles SL, Rankin G, Valentovic M, Denning KL, Tirona MT, Finch PT, Hess JA, Dasgupta P. Anticancer Activity of Region B Capsaicin Analogs. Journal of medicinal chemistry. 2023 Apr 13;66(7):4294-4323. Epub 2023 Mar 31. PMID: 37000154
  • Richbart SD, Merritt JC, Nolan NA, Dasgupta P. Acetylcholinesterase and human cancers. Advances in cancer research. 2021;152:1-66. Epub 2021 Jun 21. PMID: 34353435
  • Richbart SD, Friedman JR, Brown KC, Gadepalli RS, Miles SL, Rimoldi JM, Rankin GO, Valentovic MA, Tirona MT, Finch PT, Hess JA, Dasgupta P. Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy. Journal of medicinal chemistry. 2021 Feb 11;64(3):1346-1361. Epub 2021 Jan 28. PMID: 33508189
  • Rollyson WD, Stover CA, Brown KC, Perry HE, Stevenson CD, McNees CA, Ball JG, Valentovic MA, Dasgupta P. Bioavailability of capsaicin and its implications for drug delivery. Journal of controlled release : official journal of the Controlled Release Society. 2014 Dec 28;196:96-105. Epub 2014 Oct 12. PMID: 25307998
  • Olfert IM, DeVallance E, Hoskinson H, Branyan KW, Clayton S, Pitzer CR, Sullivan DP, Breit MJ, Wu Z, Klinkhachorn P, Mandler WK, Erdreich BH, Ducatman BS, Bryner RW, Dasgupta P, Chantler PD. Chronic exposure to electronic cigarettes results in impaired cardiovascular function in mice. Journal of applied physiology (Bethesda, Md. : 1985). 2018 Mar 1;124(3):573-582. Epub 2017 Nov 2. PMID: 29097631
  • Brown KC, Light RS, Modi KJ, Conely KB, Sugrue AM, Cox AJ, Miles SL, Valentovic MA, Dasgupta P. An Improved Protocol for the Matrigel Duplex Assay: A Method to Measure Retinal Angiogenesis. Bio-protocol. 2023 Dec 5;13(23):e4899. doi: 10.21769/BioProtoc.4899. eCollection 2023 Dec 5. PMID: 38094254