Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition

Abstract

Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras.

New insights into pancreatic cancer stem cells

“…Together, blockade of hedgehog and mTOR signaling along with standard chemotherapy was found to eliminate pancreatic CSCs [80] . Another hedgehog antagonist Vismodegib (GDC-0449), inhibits pancreatic CSC characteristics in vitro [81] . Using GDC-0449, a human phase I clinical trial is ongoing [82] , which preliminarily suggest that GDC-0449 has good safety profile and antitumor activity for some of the locally advanced or metastatic solid tumors.…”

Modulation of miRNAs by Natural Agents: Nature’s way of dealing with cancer

“…The underlying mechanism of apoptosis induction was closely related to the downregulation of oncogenic miR-27a [103] . In another study, quercetin, when used with catechins, enhanced the expression of let-7 in pancreatic cancer cells followed by K-ras inhibition and reduction of the advancement of pancreatic cancer [55] . Furthermore, the upregulation of miR-146a, a negative regulator of NF-B activation, by quercetin protects CCD-180Co colonic myofibroblast cells against ROS [104] .…”

“…A number of reports, including some from our laboratory, have documented the modulation of miRNAs by natural agents [52][53][54][55][56] . Since epigenetic alterations play important roles in aberrant expression of several miRNAs in cancer cells, natural agents are now being investigated for their ability to reverse these changes that will ultimately lead to inhibition of tumor growth, invasiveness and metastasis.…”

“…Both SOX9 and aldehyde dehydrogenase 1 (ALDH1) are also identified as targets of miR-140 and miR-140 overexpression downregulated the protein levels in both targets [121] . Recently, sulforaphane was reported to complement with quercetin and catechins in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition [55] . Further research is warranted to firmly establish these research findings and explore the possibility of the use of sulforaphane as a cancer therapeutic adjuvant option.…”

Kurkumi̇n, Kuerseti̇n Ve Çay Kateşi̇nleri̇ni̇n Anti̇-Kanser Etki̇leri̇

“…İnsan laringeal Hep-2 hücrelerinde yapılan bir başka çalışmada sisplatin ile indüklenen apoptozu %16.3 oranında arttırdığı gösterilmiştir (77). Pankreatik duktal adenokarsinoma hücrelerinde, özellikle sülforafan ve yeşil çay kateşinleri gibi farmasötik moleküller ile sinerjistik etki gösterdiği de bildirilmiştir (78). Ayrıca, kuersetinin sisplatin ve oksaliplatin ile kombinasyonunun over tümörü modellerinde ilaç direncinin kırılmasını sağladığı gösterilmiştir (79).…”