Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

Abstract

Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibited proliferation by inducing G0/G1 phase cell cycle arrest, apoptosis and autophagy in CRC cells. Repression of autophagy with autophagy inhibitors chloroquine (CQ) and Bafilomycin A1 (Baf-A1) enhanced the anti-CRC effects of IATL, suggesting that IATL induces cytoprotective autophagy in CRC cells. Mechanistic studies revealed that IATL lowered protein levels of phospho-AKT (Ser473), phospho-mTOR (Ser2448), phospho-70S6K (Thr421/Ser424) in CRC cells. Inhibition of AKT and mTOR activities using LY294002 and rapamycin, respectively, potentiated the inductive effects of IATL on autophagy and cell death. In vivo studies showed that IATL suppressed HCT116 tumor growth without affecting the body weight of mice. In consistent with the in vitro results, IATL lowered protein levels of Bcl-2, Bcl-XL, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and phsopho-70S6K (Thr421/Ser424), whereas upregulated protein levels of cleaved-PARP and LC3B-II in HCT116 tumors. Collectively, our results demonstrated that in addition to inhibiting proliferation, inducing G0/G1-phase cell cycle arrest and apoptosis, IATL initiates cytoprotective autophagy in CRC cells by inhibiting the AKT/mTOR signaling pathway. These findings provide an experimental basis for the evaluation of IATL as a novel medication for CRC treatment.

Water extract of cacumen platycladi promotes hair growth through the Akt/GSK3β/β-catenin signaling pathway

“…Hence, the WECP treatment promoted cell cycle progression ( Figures 2B, C ). The proteins, Cyclin A, CDK2, CDK4, and P21, regulate cell cycle progression from G0/G1 to S ( Li et al, 2022 ). We then quantified these cell cycle-related proteins by western blotting to verify the foregoing results.…”

“…The DPCs cycle was detected by propidium iodide (PI) staining and flow cytometry ( Li et al, 2022 ). Briefly, DPCs were seeded in six-well plates at a density of 1.5 × 10 5 /well and treated with various WECP concentrations for 24 h. The following day, the cells were harvested, washed with phosphate-buffered saline (PBS), and centrifuged (5425 R; Eppendorf, Germany).…”

Polyphyllin II Induces Protective Autophagy and Apoptosis via Inhibiting PI3K/AKT/mTOR and STAT3 Signaling in Colorectal Cancer Cells

“…Cellular proliferation was determined by clone formation and 5′-Ethynyl-2′-deoxyuridine (EdU) incorporation assays as described previously [ 34 ]. For the colony formation assay, 800 cells were plated in 6-well plates and then incubated with different concentrations of PPII (0.5, 1, and 2 μM) for 24 h. Thereafter, the cells were cultured with fresh medium for ~12 days before being stained with 0.3% crystal violet.…”

“…All mice were maintained in individual ventilated cages in an animal handling room at the Hong Kong Baptist University. A xenograft mouse model was established as described previously [ 34 ]. Briefly, each mouse was inoculated subcutaneously in the flank with the HCT116 cells (2 × 10 6 /mice).…”

Sesquiterpene lactones as emerging biomolecules to cease cancer by targeting apoptosis

“…Isoalantolactone (IAL) is a sesquiterpene lactone naturally found in the roots of Inula helenium L. with cytotoxicity against different cancer cells. Li et al (2022) observed that IAL induces G0/G1 phase cell cycle arrest, apoptosis, and autophagy in colorectal cancer (CRC) cell lines, including HCT116 and SW620. Pro-apoptotic activity of IAL in these cancer cell lines was shown by downregulation of anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 as well as downregulation of pro-apoptotic protein Bax and activation of PARP enzyme in both cancer cell lines.…”