Curcumin Suppresses Metastasis via Sp-1, FAK Inhibition, and E-Cadherin Upregulation in Colorectal Cancer.

Colorectal cancer (CRC) is a serious public health problem that results due to changes of diet and various environmental stress factors in the world. Curcumin is a traditional medicine used for treatment of a wide variety of tumors. However, antimetastasis mechanism of curcumin on CRC has not yet been completely investigated. Here, we explored the underlying molecular mechanisms of curcumin on metastasis of CRC cells in vitro and in vivo. Curcumin significantly inhibits cell migration, invasion, and colony formation in vitro and reduces tumor growth and liver metastasis in vivo. We found that curcumin suppresses Sp-1 transcriptional activity and Sp-1 regulated genes including ADEM10, calmodulin, EPHB2, HDAC4, and SEPP1 in CRC cells. Curcumin inhibits focal adhesion kinase (FAK) phosphorylation and enhances the expressions of several extracellular matrix components which play a critical role in invasion and metastasis. Curcumin reduces CD24 expression in a dose-dependent manner in CRC cells. Moreover, E-cadherin expression is upregulated by curcumin and serves as an inhibitor of EMT. These results suggest that curcumin executes its antimetastasis function through downregulation of Sp-1, FAK, and CD24 and by promoting E-cadherin expression in CRC cells.

The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate < 0.05) that are dominantly involved in the cell cycle, apoptosis and adhesion-related biological signalling, including mitogen-activated protein kinase, focal adhesion and tight junction pathways, indicating the diverse effects of andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

Potential Therapeutic Role of Z-Isochaihulactone in Lung Cancer through Induction of Apoptosis via Notch Signaling.

Lung cancer is one of the leading causes of cancer death in worldwide and required for novel therapeutic strategy. Our previous research demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) and its component isochaihulactone induce antiproliferative and apoptotic effects on the lung adenocarcinoma cell line. Structural analysis has identified isochaihulactone as a lignan, with a chiral center and two racemic forms (Z-isochaihulactone and E-isochaihulactone). In this study, Z-isochaihulactone displayed significantly higher tumor cytotoxicity than E-isochaihulactone in A549 cells. The notch signaling pathway plays a pivotal role in determination of cell fate during development, while in lung cancer, it might have oncogenic or tumor-suppressive controversial functions. We showed that Z-isochaihulactone induced morphological changes in the A549 cells, inhibited cell growth, and arrested the cell cycle at the G2/M phase. It also induced upregulation of the active form of Notch1 (notch intracellular domain, NICD), which further induced p21 and c-Myc expression in time- and dose-dependent manners. Administrations of Z-isochaihulactone in nude mice can significantly inhibit tumor growth due to enhancement of NICD expression confirmed by immunohistochemical analysis. Taken together, our results supported that Z-isochaihulactone can efficiently inhibit tumorigenicity and be a potential compound for therapy.

Rutin, a Flavonoid That Is a Main Component of Saussurea involucrata, Attenuates the Senescence Effect in D-Galactose Aging Mouse Model.

Saussurea involucrata (Kar. et Kir.), known as the snow lotus, grows in the Tian Shan and A'er Tai areas of China. It has recently been reported that the ethyl acetate extract of S. involucrata (SI-2) can inhibit proliferation and induce apoptosis in PC-3 human prostate cancer cells. This study investigated the protective effect of ethyl acetate extract of S. involucrata (SI-2) or rutin, a flavonoid extracted from ethyl acetate extract of S. involucrata (SI-2), on D-galactose- (D-gal-) induced brain injury in mice. Administering SI-2 or rutin (30 mg/kg/d and 30 mg/kg/d) for 6 weeks, concomitant with D-gal injection, significantly increased superoxide dismutase and glutathione peroxidase activities and decreased the MDA level in plasma. Furthermore, the result showed that the percentages of cleaved caspase-3 and PARP in the D-gal-treated mice were much higher than those in the control. Pretreatment using SI-2 or rutin decreased the expression of cyclooxygenase-2 via downregulation of NF-kappaB, resulting in a decrease in lipid peroxidation. Furthermore, our results also showed that oral administration of rutin to these mice significantly improved behavioral performance in a step-through passive avoidance task and these results suggest that SI-2 or rutin exerts potent antiaging effects on D-gal in mice via antioxidative mechanisms.

Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models. METHODS/PRINCIPAL FINDINGS: After screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell. CONCLUSIONS/SIGNIFICANCE: Curcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.

Extended O6-methylguanine methyltransferase promoter hypermethylation following n-butylidenephthalide combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on inhibition of human hepatocellular carcinoma cell growth.

Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O(6)-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs.