Mechanism of a Novel Camptothecin-Deoxycholic Acid Derivate Induced Apoptosis against Human Liver Cancer HepG2 Cells and Human Colon Cancer HCT116 Cells

Abstract

Background: Camptothecin (CPT) is known as an anticancer drug in traditional Chinese medicine. However, due to the lack of targeting, low solubility, and instability of CPT, its therapeutic applications are hampered. Therefore, we synthesized a series of CPT-bile acid analogues that obtained a national patent to improve their tumour-targeting chemotherapeutic effects on liver or colon cancers. Among these analogues, the compound G2 shows high antitumor activity with enhanced liver targeting and improved oral absorption. It is significant to further investigate the possible anticancer mechanism of G2 for its further clinical research and application. Objective: We aimed to unearth the anticancer mechanism of G2 in HepG2 and HCT116 cells. Methods: Cell viability was measured using MTT assay; cell cycle, Mitochondrial Membrane Potential (MMP), and cell apoptosis were detected by flow cytometer; ROS was measured by Fluorescent Microplate Reader; the mRNA and protein levels of cell cycle-related and apoptosis-associated proteins were examined by RT-PCR and western blot, respectively. Results: We found that G2 inhibited cells proliferation of HepG2 and HCT116 remarkably in a dosedependent manner. Moreover, G2-treatment led to S and G2/M phase arrest in both cells, which could be elucidated by the change of mRNA levels of p21, p27 and Cyclin E and the increased protein level of p21. G2 also induced dramatically ROS accumulated and MMP decreased, which contributed to the apoptosis through activation of both the extrinsic and intrinsic pathways via changing the genes and proteins expression involved in apoptosis pathway in both of HepG2 and HCT116 cells. Conclusion: These findings suggested that the apoptosis in both cell lines induced by G2 was related to the extrinsic and intrinsic pathways.

SYNTHESIS, CHARACTERIZATION AND CYTOTOXICITY EVALUATION OF Ni(II), Cu(II) AND Zn(II) COMPLEXES WITH DEOXYCHOLATE LIGAND

“…In the recent years, potential anticancer properties of NaDCA have gained increasing attention because of at least two reasons: (i) NaDCA has been reported to inhibit proliferation and to induce apoptosis in cells obtained from human colon cancer [48,49] and gastric carcinoma [50]; (ii) coupling with bile acid (such as deoxycholic acid) moieties has been suggested to be a promising strategy for liver-targeted drug delivery due to the presence of bile acid receptors on hepatocytes [51]. Deoxycholic acid modified conjugates have been developed and proposed as suitable novel carriers for anticancer drugs including epirubicin and paclitaxel [52,53].…”

Establishment of a prognosis Prediction Model Based on Pyroptosis-Related Signatures Associated With the Immune Microenvironment and Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma

“…Camptothecin is a natural anticancer drug in traditional Chinese medicine. Xiao et al found that the Camptothecin analogue G2 could induce apoptosis in liver cancer and colon cancer cell lines by inducing ROC accumulation and reducing MMP (37). Galley et al reported two types of Camptothecin analogues (CPT-11 and 9-AC), which showed a remarkable survival extension in an orthotopic model of late-stage renal cancer tissue (38).…”

Establishment of a prognosis prediction model based on pyroptosis-related signatures associated with the immune microenvironment and molecular heterogeneity in clear cell renal carcinoma

“…Xiao et al found that the Camptothecin analogue G2 could induce apoptosis in liver cancer and colon cancer cell lines by inducing ROC accumulation and reducing MMP 28 . Galley et al reported two types of Camptothecin analogues CPT-11 and 9-AC, which showed a marked survival advantage in an orthotopic model of advanced renal cancer 29 .…”