Berry anthocyanidins synergistically suppress growth and invasive potential of human non-small-cell lung cancer cells.
Berry anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) have increasingly been explored for their anticancer effects; however, their combinatorial effects as a mixture, as present in blueberry, bilberry and Indian blackberry ('Jamun') remain untested. In this study, we demonstrate for the first time that the combination of suboptimal concentrations of equimolar anthocyanidins synergistically inhibited growth of two aggressive non-small-cell lung cancer cell lines, with minimal effects on non-tumorigenic cell viability. The induction of cell-cycle arrest, apoptosis and suppression of NSCLC cell invasion and migration were also significantly greater with the mixture than individual anthocyanidins. The superior effects of the combinatorial treatment presumably resulted from its effects on the oncogenic Notch and WNT pathways and their downstream targets (β-catenin, c-myc, cyclin D1, cyclin B1, pERK, MMP9 and VEGF proteins), enhanced cleavage of the apoptotic mediators Bcl2 and PARP and enhanced inhibition of TNFα-induced NF-kappa B activation. In vivo, both the native mixture of anthocyanidins from bilberry (0.5mg/mouse) and the most potent anthocyanidin, delphinidin (1.5mg/mouse) significantly inhibited the growth of H1299 xenografts in nude miceby ≈60%. Notably, the effective dose of delphinidin in the anthocyanidin mixture was 8-fold lower than delphinidin alone, further emphasizing synergism. Our results thus demonstrate therapeutic potential of berries rich in this mixture of diverse anthocyanidins for non-small-cell lung cancer treatment and to prevent its future recurrence and metastasis.
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Hina
H
Kausar
Jeyaprakash
J
Jeyabalan
Farrukh
F
Aqil
Deepika
D
Chabba
Jasmeen
J
Sidana
Inder P
IP
Singh
Ramesh C
RC
Gupta
D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D005638:Fruit / Q000737:chemistry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000872:Anthocyanins; D016328:NF-kappa B; D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D011065:Poly(ADP-ribose) Polymerases; C017185:delphinidin