Abstract
The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action. In vitro, 4bb is a significantly more potent SIRT1 inhibitor, compared to β-naphthols such as sirtinol, cambinol. Increasing concentration of 4bb decrease viability of colon cancer cells but, does not affect the viability of normal dermal fibroblasts depicting cancer cell specificity. Further, 4bb treatment increased p53 acetylation, Bax expression and induced caspase 3 cleavage suggesting that the death of HCT116 colon cancer cells occur through intrinsic pathway of apoptosis. Overall, our results presents 4bb as a new class of human SIRT1 inhibitor and suggest that inhibition of SIRT1 by 4bb induces apoptosis of colon cancer cells at least in part via activating p53...Continue Reading
References
May 19, 2001·European Journal of Biochemistry·S R Grossman
Aug 3, 2001·The Journal of Biological Chemistry·C M GrozingerS L Schreiber
Oct 24, 2001·Cell·J LuoW Gu
Oct 24, 2001·Cell·H VaziriR A Weinberg
Oct 10, 2003·The Journal of Biological Chemistry·Maki HiraoAntonio Bedalov
Feb 14, 2004·Science·Jerry E ChipukDouglas R Green
Nov 5, 2005·Cell·Wen Yong ChenStephen B Baylin
Dec 16, 2005·Molecular and Cellular Biology·Jonathan M SolomonL Julie Huber
Jul 29, 2006·Cell·Valter D Longo, Brian K Kennedy
Nov 3, 2006·Genes & Development·Marcia C Haigis, Leonard P Guarente
Apr 24, 2007·The Biochemical Journal·Shaday Michan, David Sinclair
Jul 20, 2007·Cancer Research·Derek M HuffmanTim R Nagy
Feb 27, 2009·Cancer Research·Tao LiuGlenn M Marshall
May 13, 2009·The Journal of Biological Chemistry·Neha KabraJiandong Chen
Sep 16, 2009·Carcinogenesis·Shikhar SharmaPeter A Jones
Apr 8, 2010·Molecular Cancer Therapeutics·Barrie PeckEric W-F Lam
Apr 26, 2011·Methods in Molecular Biology·Johan van MeerlooJacqueline Cloos
Sep 16, 2011·Human Pathology·Tadao NakazawaRyohei Katoh
Mar 27, 2012·Bioorganic & Medicinal Chemistry Letters·Soo Hyuk ChoiRichard B Silverman
Jan 23, 2013·Molecular Cancer Therapeutics·Simone PortmannDeborah Stroka
Jun 5, 2013·Chemical Communications : Chem Comm·Ali NakhiManojit Pal
Sep 7, 2013·Korean Journal of Pathology·Wonkyung JungBaek-Hui Kim
Sep 11, 2013·Genes & Cancer·James T Lee, Wei Gu
Feb 12, 2014·Oncology Research·Takunori UenoIchinosuke Hyodo
May 13, 2014·Medical Oncology·Liang LvShan Wang
Jun 26, 2014·Future Medicinal Chemistry·Jing HuHening Lin
Oct 15, 2014·Cancer Letters·Min Gyeong CheonJa-Eun Kim
Dec 3, 2014·European Journal of Medicinal Chemistry·Juliana CogoCelso Vataru Nakamura
Oct 27, 2015·BMC Cancer·Kosuke SakitaniKazuhiko Koike
Feb 24, 2016·Scientific Reports·Wenwen ZhangXiaoxiang Guan
Citations
Apr 13, 2018·Future Medicinal Chemistry·Ziyan ZhouXiaoming Zha
Jan 2, 2018·World Journal of Gastroenterology : WJG·Ferenc SiposGyörgyi Műzes
Apr 10, 2020·Anti-cancer Agents in Medicinal Chemistry·Malavattu G PrasadManojit Pal
Aug 2, 2019·Cells·Wolfgang EberhardtKristina Haeussler
Feb 12, 2019·British Journal of Cancer·Giulia Dell'OmoPaolo Ciana
Jul 24, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Berin Karaman MayackFidele Ntie-Kang
Jul 28, 2020·European Journal of Medicinal Chemistry·Hanna LaaroussiSylvain Broussy
Nov 27, 2021·Molecular Oncology·Yeon-Hwa LeeYoung-Joon Surh