Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1α Degradation

Abstract

Micheliolide (MCL) has shown promising anti-inflammatory and anti-tumor efficacy. However, whether and how MCL enhances the sensitivity of non-small-cell lung cancer (NSCLC) to radiotherapy are still unknown. In the present paper, we found that MCL exerted a tumor cell killing effect on NSCLC cells in a dose-dependent manner, and MCL strongly sensitized p53-deficient NSCLC cells, but not the cells with wild-type p53 to irradiation (IR). Meanwhile, MCL markedly inhibited the expression of hypoxia-inducible factor-1α (HIF-1α) after IR and hypoxic exposure in H1299 and Calu-1 cells rather than in H460 cells. Consistently, radiation- or hypoxia-induced expression of vascular endothelial growth factor (VEGF) was also significantly inhibited by MCL in H1299 and Calu-1 cells, but not in H460 cells. Therefore, inhibition of the HIF-1α pathway might, at least in part, contribute to the radiosensitizing effect of MCL. Further study showed that MCL could accelerate the degradation of HIF-1α through the ubiquitin-proteosome system. In addition, the transfection of wild-type p53 into p53-null cells (H1299) attenuated the effect of MCL on inhibiting HIF-1α expression. These results suggest MCL effectively sensitizes p53-deficient NSCLC cells to IR in a manner of inhibiting the HIF-1α pathway via promoting HIF-1α degradation, and p53 played a negative role in MCL-induced HIF-1α degradation.

Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma

“…MCL, as a natural active compound with therapeutic efficacy toward inflammation and multiple cancers, belongs to guaianolide sesquiterpene lactone, which has been identified as the derivative of parthenolide (PTL) discovered in the flowers of Michelia compressa and Michelia champaca plants [ 36 , 37 ]. With better stability than PTL, MCL can selectively inhibit the activity of acute myelogenous leukemia stem and progenitor cells.…”

Dimethylaminomicheliolide Sensitizes Cancer Cells to Radiotherapy for Synergistic Combination with Immune Checkpoint Blockade

“…[38] It has been reported that parthenolide sensitized prostate cancer cells DU145 and PC3 to radiation treatment [39] and MCL enhanced radiosensitivity of non-smallcell lung cancer cells. [40] In this study, we investigated the effects of DMAMCL on murine colorectal carcinoma cell CT26 and glioblastoma cell GL261, with or without X-ray irradiation (Figure 1a The radiosensitization effects of DMAMCL on cancer cells were further confirmed by clonogenic assays (Figure 1c,d and Figure S1a,b, Supporting Information). Both CT26 and GL261 cells dosed with 10 μM DMAMCL with X-ray showed significantly fewer spot forming cells compared to without DMAMCL treatment, with the REF 10 (radiation enhancement factor at 10% survival dose) values of 1.27 and 1.4, respectively, indicating impaired cell proliferation abilities after treatment with DMAMCL(+).…”

Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha

“…Micheliolide also sensitizes lung cancer cells to irradiation, owing to its prohibitory action on HIF-1α. Notably, micheliolide was confirmed to facilitate HIF-1α degradation [ 177 ]. Although it is required to uncover molecular mechanisms accounting for micheliolide-mediated HIF-1α degradation, STAT3 can be involved in HIF-1α regulation, since its activity is inhibited by micheliolide [ 189 ] ( Figure 3 and Table 3 ).…”