Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to quite complicated the molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on CHM-derived anti-HCC compounds, especially their underlying pharmacological mechanisms.
A systematic search of CHM-derived anti-HCC compounds was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic database (Wanfang and CNKI database).
In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed.
Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM.
"Hepatocellular carcinoma (HCC) exhibits one of the highest incidences of morbidity and mortality worldwide (1), and presents the predominant histological subtype of primary liver cancer (2). As postsurgical recurrence of HCC is frequent and often fatal, surgery and liver transplant offer limited treatment options for HCC (3,4). Consequently, it is important to identify an effective drug therapy for the treatment of HCC. "
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is a life-threatening disease that is known to exhibit a poor prognosis. Therefore, it is important to identify an effective drug therapy for the treatment of HCC. Dihydromyricetin (DHM) is a flavonoid compound, isolated from the classical Chinese herb Ampelopsis grossedentata, which exhibits multiple pharmacological activities, including anticancer effects. In this study, the anticancer effect of DHM was investigated in nine different types of HCC cell lines via cell proliferation and immunoassays, as well as apoptosis detection. Two immortalized normal human liver cell lines were utilized to determine hepatotoxicity. The results revealed that DHM significantly inhibited cell proliferation and induced cell apoptosis in the HCC cell lines. However, DHM exhibited no cytotoxicity to normal human hepatic cell lines. Furthermore, it was found that DHM induced cell apoptosis in a p53-dependent manner. DHM upregulated p53 expression, and the upregulation of p53 increased the levels of the cleaved caspase-3 protein, directly inducing cell apoptosis. These results indicate that DHM is a promising candidate for the treatment of HCC.
"An interesting issue, which pathway might be related to celastrol’s inhibition of ICAM-1, thus attracted our attention. To address it, we observed alterations of the main signaling molecules already reported as celastrol’s targets, including MEK1, ERK1, NF-κB, JNK, p38, and STAT1 , – in cells treated with ATRA and celastrol, and these agents’ roles in celastrol’s ICAM-1 inhibition. "
[Show abstract][Hide abstract] ABSTRACT: All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.
PLoS ONE 08/2014; 9(8):e105131. DOI:10.1371/journal.pone.0105131 · 3.23 Impact Factor
"The availability of well curated databases of ingredients of traditional Chinese medicines has opened up new avenues for molecular screening as well as in-silico studies, including target-based docking (Chen et al., 2006; Fang et al., 2008; Chen, 2011; Zhou, Xie & Yan, 2011). In depth screens of Chinese medicine derived compounds have been performed for a variety of pathophysiologies, including cancer (Hu et al., 2013), inflammatory diseases (Han & Guo, 2012; Su & Hsieh, 2011), cardiovascular diseases (Wang et al., 2013) and infections (Jiang, Deng & Wu, 2013), just to name a few. These databases are being extensively used for therapeutic development (Cheng et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Background. Traditional Chinese medicine encompasses a well established alternate system of medicine based on a broad range of herbal formulations and is practiced extensively in the region for the treatment of a wide variety of diseases. In recent years, several reports describe in depth studies of the molecular ingredients of traditional Chinese medicines on the biological activities including anti-bacterial activities. The availability of a well-curated dataset of molecular ingredients of traditional Chinese medicines and accurate in-silico cheminformatics models for data mining for antitubercular agents and computational filters to prioritize molecules has prompted us to search for potential hits from these datasets.
Results. We used a consensus approach to predict molecules with potential antitubercular activities from a large dataset of molecular ingredients of traditional Chinese medicines available in the public domain. We further prioritized 160 molecules based on five computational filters (SMARTSfilter) so as to avoid potentially undesirable molecules. We further examined the molecules for permeability across Mycobacterial cell wall and for potential activities against non-replicating and drug tolerant Mycobacteria. Additional in-depth literature surveys for the reported antitubercular activities of the molecular ingredients and their sources were considered for drawing support to prioritization.
Conclusions. Our analysis suggests that datasets of molecular ingredients of traditional Chinese medicines offer a new opportunity to mine for potential biological activities. In this report, we suggest a proof-of-concept methodology to prioritize molecules for further experimental assays using a variety of computational tools. We also additionally suggest that a subset of prioritized molecules could be used for evaluation for tuberculosis due to their additional effect against non-replicating tuberculosis as well as the additional hepato-protection offered by the source of these ingredients.
Santosh K. Misra, Goutam Ghoshal, Manas R. Gartia, Zhe Wu, Arun K. De, Mao Ye, Corinne R. Bromfield, Emery M. Williams, Kuldeep Singh, Krishnarao V. Tangella, Laurie Rund, Klaus J. Schulten, Lawrence B. Schook, Partha S. Ray, Everette C. Burdette, Dipanjan Pan
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