Common Botanical Compounds Inhibit the Hedgehog Signaling Pathway in Prostate Cancer

Abstract

Many botanical compounds have been proposed to prevent cancer. We investigated the cancer treatment and prevention abilities of apigenin, baicalein, curcumin, epigallocatechin 3-gallate (EGCG), genistein, quercetin, and resveratrol both in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice as well as in vitro in prostate cancer cell lines. In our experiments, these seven compounds act similarly to the Hedgehog antagonist cyclopamine, a teratogenic plant alkaloid, which had been previously shown to "cure" prostate cancer in a mouse xenograft model. With IC 50 values ranging from <1 to 25 μmol/L, these compounds can inhibit Gli1 mRNA concentration by up to 95% and downregulate Gli reporter activity by 80%. We show that four compounds, genistein, curcumin, EGCG, and resveratrol, inhibit Hedgehog signaling as monitored by real-time reverse transcription-PCR analysis of Gli1 mRNA concentration or by Gli reporter activity. Three compounds, apigenin, baicalein, and quercetin, decreased Gli1 mRNA concentration but not Gli reporter activity. Our results show that these compounds are also able to reduce or delay prostate cancer in vivo in TRAMP mice. All seven compounds, when fed in combination as pure compounds or as crude plant extracts, inhibit well-differentiated carcinoma of the prostate by 58% and 81%, respectively. In vitro, we show that all seven compounds also inhibit growth in human and mouse prostate cancer cell lines. Mechanistically, we propose the Hedgehog signaling pathway to be a direct or indirect target of these compounds. These botanicals at pharmacologic concentrations are potentially safer and less expensive alternatives to cyclopamine and its pharmaceutical analogues for cancer therapy. Cancer Res; 70(8); 3382-90. ©2010 AACR.

Curcumin inhibits hypoxia-induced epithelial-mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway

“…In addition, curcumin also enhanced the anti-tumor effects of cisplatin and γ-rays by targeting pathways that are crucial for tumor survival. Slusarz et al (29) reported that curcumin caused major reductions in GLI1 mRNA concentrations in transgenic prostate carcinoma mice. A recent study also revealed that resveratrol and curcumin synergistically caused apoptosis in cigarette smoke induced breast cancer cells through p21 (Waf/Cip1) mediated inhibition of Hedgehog-GLI cascade (30).…”

Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis

“…Numerous studies in the literature have indicated that resveratrol exhibits anticancer, anti-inflammatory, anti-oxidative and antiasthmatic effects (26,27,35,36), suppresses metastasis in several cancers (37), inhibits platelet aggregation in cardiovascular diseases, and regulates mucin, inflammatory mediators [monocyte chemoattractant protein-1, interleukin (IL)-6 and IL-8] and matrix-metalloprotease-9 expression in chronic obstructive pulmonary disease (38)(39)(40). Another study revealed that resveratrol inhibits the Hh signaling pathway in prostate cancer (32). These beneficial properties mean that resveratrol can be used as a potential health-benefiting compound in the manufacture of pharmaceuticals, cosmetics and nutraceuticals.…”

“…In particular, study findings have indicated that resveratrol inhibits EMT in lung, pancreatic and breast cancer (29)(30)(31), and that it is also able to suppress the Hh signaling pathway in prostate carcinoma (32). In addition, resveratrol has been identified as being able to prevent, reverse or delay carcinogenesis.…”

Failure of Pancreatic Cancer Chemotherapy: Consequences of Drug Resistance Mechanisms

“…Previously, genistein was known to affect the activation of NFκB via the Akt pathway (El-Rayes, et al, 2006), which have been shown to be involved in pancreatic cancer drug resistance. Natural compounds (e.g., genistein, curcumin) have also been shown to inhibit the hedgehog and Notch signaling which provide the cancer cells with stem-cell like property of self-renewal and resistance (Slusarz, et al, 2010). A recent study noted upregulation of FOXM1, increased EMT, and cancer stem cell phenotype in pancreatic cancer (Bao, et al, 2011a).…”