The dietary compound luteolin inhibits pancreatic cancer growth by targeting BCL-2

Food & Function
Zhimei LiHua Li

Abstract

Overexpression of the prosurvival protein BCL-2 contributes to malignant cell initiation, progression and resistance to treatment. Agents that function as its natural antagonists targeting BCL-2 must provide therapeutic benefit. In SW1990 pancreatic cancer cells, amplified BCL-2 was observed, which was believed to offer advantages for malignant cell survival and lead to poor patient outcome. Using structure-based virtual ligand screening, luteolin was found to be a natural small-molecule inhibitor of BCL-2, which exhibited dose-response proapoptosis activity in a BCL-2 dependent manner in vitro. The cellular thermal shift assay (CETSA) and notably competitive binding assay by the microscale thermophoresis (MST) method provided the evidence that this flavonoid directly bound to BCL-2. Mechanistic studies revealed that luteolin (compound 1) displaced BAX from the hydrophobic cleft of BCL-2, allowing mitochondrial permeabilization, and inducing SW1990 cancer cells to die. Meanwhile, luteolin represented significant tumor growth inhibition in an SW1990 xenograft model. Collectively, luteolin is rationally proved to trigger SW1990 cells to apoptosis by targeting BCL-2, and may serve as a potential agent for this cancer therapy.

References

Aug 28, 1998·Science·A Ashkenazi, V M Dixit
Jan 28, 2004·Cell·Nika N Danial, Stanley J Korsmeyer
Jun 7, 2005·Cell·Douglas R Green
Feb 18, 2010·Molecular Cell·Jerry E ChipukDouglas R Green
Dec 15, 2010·Biochimica Et Biophysica Acta·Aisha Shamas-DinDavid W Andrews
Jan 12, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nguyen TanLisa D Belmont
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Dec 21, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andrew W RobertsRod Humerickhouse
May 23, 2012·Bioorganic & Medicinal Chemistry Letters·Heidi L PerezRobert M Borzilleri
Jun 21, 2013·Nature Reviews. Cancer·Philippe JuinMario Campone
Dec 21, 2013·Nature Reviews. Molecular Cell Biology·Peter E CzabotarJerry M Adams
Feb 8, 2014·Trends in Biochemical Sciences·Tudor MoldoveanuDouglas R Green
Jul 23, 2014·Seminars in Hematology·Mary Ann AndersonAndrew Roberts
May 9, 2015·Cell Death and Differentiation·A R D Delbridge, A Strasser
Sep 8, 2015·Nature Cell Biology·Hui-Chen ChenEmily H Cheng
Dec 8, 2015·The New England Journal of Medicine·Andrew W RobertsJohn F Seymour
Jan 30, 2016·Nature Reviews. Cancer·Alex R D DelbridgeDavid L Vaux
May 20, 2016·Scientific Reports·Weiguang SunYonghui Zhang
Oct 28, 2016·Nature·András KotschyOlivier Geneste
Feb 18, 2017·Nature Reviews. Drug Discovery·Avi AshkenaziAndrew J Souers
Nov 10, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Timothy L LochmannAnthony C Faber

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Citations

Jun 28, 2019·Frontiers in Oncology·Qingmei YeRen-Wang Jiang
Jul 29, 2020·Antioxidants·Anita ThyagarajanRavi P Sahu
Nov 7, 2019·Biomolecules·Javad Sharifi-RadWilliam C Cho
Jan 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yue YangNing Li

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Methods Mentioned

BETA
xenograft
thermal shift
gel filtration
enzyme-linked immunosorbent assay
flow cytometry
microscale thermophoresis
xenografts

Software Mentioned

ICM3
NTAnalysis
GraphPad
GraphPad Prism
Prism
ICM
MST

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