Butein and Frondoside-A Combination Exhibits Additive Anti-Cancer Effects on Tumor Cell Viability, Colony Growth, and Invasion and Synergism on Endothelial Cell Migration.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Cell Movement*/drug effects; Antineoplastic Agents/*pharmacology ; Chalcones/*pharmacology ; Endothelial Cells/*pathology ; Glycosides/*pharmacology ; Triterpenes/*pharmacology; Animals ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chick Embryo ; Drug Synergism ; Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Neoplasm Invasiveness ; Neovascularization, Pathologic/pathology ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; STAT3 Transcription Factor/metabolism ; Tumor Stem Cell Assay ; Xenograft Model Antitumor Assays

Despite the significant advances in targeted- and immuno-therapies, lung and breast cancer are at the top list of cancer incidence and mortality worldwide as of 2020. Combination therapy consisting of a mixture of different drugs taken at once is currently the main approach in cancer management. Natural compounds are extensively investigated for their promising anti-cancer potential. This study explored the anti-cancer potential of butein, a biologically active flavonoid, on two major solid tumors, namely, A549 lung and MDA-MB-231 breast cancer cells alone and in combination with another natural anti-cancer compound, frondoside-A. We demonstrated that butein decreases A549 and MDA-MB-231 cancer cell viability and colony growth in vitro in addition to tumor growth on chick embryo chorioallantoic membrane (CAM) in vivo without inducing any noticeable toxicity. Additionally, non-toxic concentrations of butein significantly reduced the migration and invasion of both cell lines, suggesting its potential anti-metastatic effect. We showed that butein anti-cancer effects are due, at least in part, to a potent inhibition of STAT3 phosphorylation, leading to PARP cleavage and consequently cell death. Moreover, we demonstrated that combining butein with frondoside-A leads to additive effects on inhibiting A549 and MDA-MB-231 cellular viability, induction of caspase 3/7 activity, inhibition of colony growth, and inhibition of cellular migration and invasion. This combination reached a synergistic effect on the inhibition of HUVECs migration in vitro. Collectively, this study provides sufficient rationale to further carry out animal studies to confirm the relevance of these compounds' combination in cancer therapy.

Mol Med Rep. 2014 Feb;9(2):763-7. (PMID: 24337484)
Mol Med Rep. 2012 Nov;6(5):1126-32. (PMID: 22895548)
Cell. 2017 Dec 14;171(7):1678-1691.e13. (PMID: 29245013)
Eur J Pharmacol. 2011 Oct 1;668(1-2):25-34. (PMID: 21741966)
Biochim Biophys Acta. 2014 Apr;1845(2):136-54. (PMID: 24388873)
Nutrients. 2018 May 01;10(5):. (PMID: 29724012)
BMC Complement Altern Med. 2016 Apr 27;16:122. (PMID: 27121110)
J Exp Clin Cancer Res. 2014 Jun 11;33:51. (PMID: 24919544)
BMC Complement Altern Med. 2015 Dec 22;15:445. (PMID: 26694191)
Mol Pharmacol. 2009 Mar;75(3):525-33. (PMID: 19103760)
Expert Opin Ther Targets. 2016 Sep;20(9):1035-43. (PMID: 27232533)
Drug Discov Ther. 2017 May 30;11(2):110-114. (PMID: 28442678)
Sci Rep. 2016 Feb 18;6:21144. (PMID: 26888313)
Mar Drugs. 2018 Feb 19;16(2):. (PMID: 29463049)
Oncol Rep. 2015 Jun;33(6):3085-92. (PMID: 25962638)
Int J Cancer. 2016 May 15;138(10):2450-65. (PMID: 26695519)
Med Princ Pract. 2016;25 Suppl 2:41-59. (PMID: 26679767)
Oncotarget. 2016 Apr 5;7(14):18651-64. (PMID: 26919107)
Oncol Lett. 2018 Nov;16(5):6615-6623. (PMID: 30344763)
J Agric Food Chem. 2014 Sep 17;62(37):9109-17. (PMID: 25137351)
Transl Oncol. 2015 Apr;8(2):97-105. (PMID: 25926075)
Br J Pharmacol. 2020 Mar;177(6):1409-1423. (PMID: 31368509)
FEBS Lett. 2008 Jun 11;582(13):1821-8. (PMID: 18472007)
Food Chem Toxicol. 2018 Feb;112:1-10. (PMID: 29258953)
Biochem Pharmacol. 2010 Nov 15;80(10):1553-62. (PMID: 20699088)
Phytomedicine. 2017 Feb 15;25:118-127. (PMID: 28190465)
CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338)
J Cancer Res Ther. 2019 Jul-Sep;15(5):953-960. (PMID: 31603094)
Cancer Res. 2005 Jan 1;65(1):195-202. (PMID: 15665295)
J Agric Food Chem. 2011 Aug 24;59(16):9032-8. (PMID: 21770460)
Eur J Cancer. 2014 May;50(7):1391-8. (PMID: 24462376)
Theranostics. 2020 Aug 1;10(21):9741-9766. (PMID: 32863957)
Biomed Pharmacother. 2020 Apr;124:109821. (PMID: 31962285)
Front Oncol. 2017 Aug 14;7:167. (PMID: 28856117)
Antioxid Redox Signal. 2012 Jun 1;16(11):1195-204. (PMID: 22114764)
Clin Cancer Res. 2011 Mar 15;17(6):1425-39. (PMID: 21131551)
Ann Oncol. 2015 May;26(5):998-1005. (PMID: 25609248)
Nat Rev Drug Discov. 2013 Aug;12(8):611-29. (PMID: 23903221)
PLoS One. 2013;8(1):e53087. (PMID: 23308143)
Oncogene. 2003 Jul 3;22(27):4150-65. (PMID: 12833138)
Oncologist. 2014 May;19(5):536-44. (PMID: 24705981)
Onco Targets Ther. 2018 Apr 06;11:2007-2015. (PMID: 29670376)
Evid Based Complement Alternat Med. 2013;2013:943187. (PMID: 23840271)

31M473 College of Medicine and Health Sciences, United Arab Emirates University

Keywords: STAT3; angiogenesis; breast cancer; butein; frondoside-A; invasion; lung cancer; tumor growth; viability

0 (Antineoplastic Agents)
0 (Chalcones)
0 (Glycosides)
0 (STAT3 Transcription Factor)
0 (Triterpenes)
0 (frondoside A)
4WVS5M0LGF (butein)
EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
EC 3.4.22.- (Caspase 3)
EC 3.4.22.- (Caspase 7)

Date Created: 20220111 Date Completed: 20220203 Latest Revision: 20220203

20221213

PMC8745659

10.3390/ijms23010431

35008855