Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs

Abstract

Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-β1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC50 values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…Sensitization to cisplatin and erlotinib (garcinol), suppression of cancer stem cells (garcinol), increased TRAIL‐based apoptosis (garcinol)…”

“…Upregulation of let‐7c and miR‐200c (garcinol), suppression of Wnt/ β ‐catenin/STAT3 and ALDH1 A1 (garcinol), activation of DDIT3, induction of DR5 (garcinol), suppression of c‐FLIP (garcinol)…”

“…Non‐small cell lung cancer cells were sensitized to cisplatin and erlotinib treatment by garcinol. This effect was mediated by miRNAs and garcinol was able to upregulate EMT‐modulating miRNAs such as let‐7c and miR‐200b . Lung cancer stem cells (LCSCs) were also targeted by garcinol and repression of the Wnt/ β ‐catenin/STAT3 signaling pathway by garcinol treatment suppressed the ability of NSCLC cells to form spheres and reduced the tumor growth in the H441 LCSC mouse xenograft model .…”

“…This effect was mediated by miRNAs and garcinol was able to upregulate EMT-modulating miRNAs such as let-7c and miR-200b. [28] Lung cancer stem cells (LCSCs) were also targeted by garcinol and repression of the Wnt/βcatenin/STAT3 signaling pathway by garcinol treatment suppressed the ability of NSCLC cells to form spheres and reduced the tumor growth in the H441 LCSC mouse xenograft model. [29] In addition, garcinol activated DDIT3 (DNA damage-inducible transcript 3) and suppressed the cancer stem cell marker ALDH1 A1 (aldehyde dehydrogenase 1 family member A1) in A549 NSCLC cells.…”

“…In vivo activity Lung cancer Sensitization to cisplatin and erlotinib (garcinol), [28] suppression of cancer stem cells (garcinol), [29,30] increased TRAIL-based apoptosis (garcinol) [54] Upregulation of let-7c and miR-200c (garcinol), [28] suppression of Wnt/β-catenin/STAT3 and ALDH1 A1 (garcinol), [29] activation of DDIT3, induction of DR5 (garcinol), [30] suppression of c-FLIP (garcinol) [54] Inhibition of H441 LCSC mouse xenograft tumor growth (garcinol) [29] Colorectal cancer…”