phenanthroindolizidine and Liver-Neoplasms

Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of survival in hepatocellular carcinoma (HCC), and provides curative option for the related drugs development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)-9,11,12,13,13a,14-hexahydro-3,6,7-trimethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinolin-14-ol (HTBPI), is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy-lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed HTBPI targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. In contrast, ectopic Akt-induced overexpression significantly abrogated inhibitory effects of HTBPI on cell viability and proliferation. Furthermore, high p-Akt (Thr 308) expression is collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p-Akt (Thr 308). This may provide potential molecular candidate by targeting Akt for the therapy of HCC patients.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Female; Humans; Indolizines; Liver Neoplasms; Male; Mice; Phenanthrolines; Proto-Oncogene Proteins c-akt

Malignant cancer is one of the most serious diseases threatening the health of human beings. Natural plant alkaloids exhibit multiple biological functions, including inhibition of cell proliferation, and may have potential anticancer activity. However, most natural alkaloids may not be suitable for human therapies owing to instability, poor dissolubility and potential side effects. To improve their anticancer activity and drug effect, the present study aimed to develop new alkaloid derivatives, the phenanthroindolizidine alkaloid compounds, and evaluated their potential antitumor effects on human cancer cells in vitro. Among the several newly synthesized analogues of phenanthroindolizidine alkaloids (PAs), the compounds YS306 and YS206 exhibited an increased growth inhibition activity on HepG2 liver cancer cells and on HCT116 and HT29 colon cancer cells, with half‑maximal inhibitory concentrations in the micromolar range. YS206 and YS306 (5 µg/ml) both significantly induced cell cycle arrest at the G2/M phase and notably decreased cell distribution at the G0/G1 and S phase. In addition, these two molecules significantly inhibited cancer cell migration, as analyzed by the wound‑healing and Transwell assays. However, neither YS306 nor YS206 exhibited observable effects on apoptosis. Therefore, chemical structure modifications of natural PAs based on anticancer activity assessments may be feasible in the development of new cancer chemotherapeutic agents.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Colonic Neoplasms; Drug Screening Assays, Antitumor; HCT116 Cells; Hep G2 Cells; HT29 Cells; Humans; Indolizines; Liver Neoplasms; Phenanthrolines