Exploration of anti-cancer effects and mechanisms of Zuo-Jin-Wan and its alkaloid components in vitro and in orthotopic HepG2 xenograft immunocompetent mice

Abstract

BackgroundZuo-Jin-Wan (ZJW), a two-herb formula consisting of Coptis chinensis (CC) and Evodia rutaecarpa (ER), is commonly used in traditional Chinese medicine for the treatment of cancers. However, the efficacies and mechanisms of ZJW and its alkaloid components on cancers are still unclear.MethodsHere we investigated the anti-cancer effects and mechanisms of ZJW, CC, ER, berberine, and evodiamine in cells and in intrahepatic xenograft mice.ResultsTreatment of HepG2 cells with ZJW, CC, ER, berberine, and evodiamine significantly displayed cytotoxic effects in a dose- and time-dependent manner. Hierarchical cluster analysis of gene expression profiles showed that CC and ZJW shared a similar mechanism for the cytotoxic effects, suggesting that CC was the active ingredient of ZJW for anti-cancer activity. Network analysis further showed that c-myc was the likely key molecule involved in the regulation of ZJW-affected gene expression. A human hepatoma xenograft model was established by intrahepatic injection of HepG2 cells containing nuclear factor-κB-driven luciferase genes in immunocompetent mice. In vivo bioluminescence imaging showed that cells had been successfully transplanted in mouse liver. Oral administration of ZJW for 28 consecutive days led to a significant decrease in the accumulation of ascites, the ratio of tumor-to-liver, and the number of transplanted cells in livers.ConclusionsIn conclusion, our findings suggested for the first time that ZJW significantly suppressed human cancer cell growth in orthotopic HepG2 xenograft-bearing immunocompetent mice. Moreover, c-myc might play a potent role in the cytotoxic mechanisms of ZJW, CC, ER, berberine, and evodiamine.

Uncovering the Anticancer Mechanisms of Chinese Herbal Medicine Formulas: Therapeutic Alternatives for Liver Cancer

“…Zuo Jin Wan (ZJW) is a well-known drug pair composed of C. chinensis Franch and Fructus rutaecarpa Benth (Wuzhuyu), which was prescribed to remove heat and dampness from liver. Recent works have identified antineoplastic activity of ZJW in several types of tumors including gastric cancer (Tang et al, 2012), colorectal cancer (Sui et al, 2013), breast cancer (Du et al, 2013), and liver cancer (Chao et al, 2011;Chou et al, 2017). The mode of action underlying the antiproliferation effect of ZJW on these malignancies involved the induction of mitochondria-dependent apoptosis (Xu et al, 2014).…”

A Potential Herbal Adjuvant Combined With a Peptide-Based Vaccine Acts Against HPV-Related Tumors Through Enhancing Effector and Memory T-Cell Immune Responses

“…The insoluble materials were removed by centrifugation at 3,000 rpm for 30 min and stored at 4 • C. Extracts were dissolved in water at a concentration of 100 mg/ml and stored at −20 • C until use. The method of preparation of CHM extract was described previously (9,13). The HPLC profile of BHSSC is shown in Figure S1.…”

“…Chinese herbal medicine (CHM) has a long history in the treatment of various human diseases, including tumors, infections, and autoimmune diseases, in Asian countries. Some studies have demonstrated that CHM may enhance antitumor activity through increasing tumor apoptosis (7)(8)(9), inhibiting angiogenesis (10), and modulating the tumor microenvironment (11). In a large-scale clinical analysis, patients with malignant tumors who sought adjunctive CHM treatment had a better overall survival rate than patients who did not undergo CHM treatment (9,(12)(13)(14).…”

“…Some studies have demonstrated that CHM may enhance antitumor activity through increasing tumor apoptosis (7)(8)(9), inhibiting angiogenesis (10), and modulating the tumor microenvironment (11). In a large-scale clinical analysis, patients with malignant tumors who sought adjunctive CHM treatment had a better overall survival rate than patients who did not undergo CHM treatment (9,(12)(13)(14). Among frequently used forms of CHM, Hedyotis diffusa Willd (Bai Hua She She Cao, BHSSC) is associated with a reduced hazard ratio for mortality risk in nasopharyngeal carcinoma and breast cancer (9,12,14).…”

“…In a large-scale clinical analysis, patients with malignant tumors who sought adjunctive CHM treatment had a better overall survival rate than patients who did not undergo CHM treatment (9,(12)(13)(14). Among frequently used forms of CHM, Hedyotis diffusa Willd (Bai Hua She She Cao, BHSSC) is associated with a reduced hazard ratio for mortality risk in nasopharyngeal carcinoma and breast cancer (9,12,14). Moreover, previous investigations have shown that H. diffusa Willd possesses important pharmacological activities and is capable of inducing apoptosis in ovarian cancer cells and inhibiting cell proliferation in hepatocellular carcinoma (15,16).…”