Chinese scientists revealed that Micheliolide (MCL) significantly sensitized p53-deficient non-small cell lung cancer (NSCLC) cells to irradiation (IR) and further uncovered how it worked.
This work was done by HAN Wei and his team from the Institute of Health & Medical Technology, Hefei Institutes of Physical Science.
Lung cancer, as a malignant tumor disease, is worldwide known for its highest incidence and mortality. Doctors and researchers have been trying to find effective cures and radiotherapy is one of them. However, in clinical use, this regular treatment is greatly limited by the radioresistance of the lung cancer cells.
MCL, a natural guaianolide sesquiterpene lactone isolated from Michelia compressa and Michelia champaca plants, presents promising therapeutic efficacy towards inflammation and multiple cancers.
In this study, the team has done a series of work and they found that MCL could significantly sensitize p53-deficient NSCLC cells to IR.
According to the researchers, MCL was effective to kill NSCLC cells and depended on its dose. When combined with IR, MCL pretreatment could strongly sensitize p53-deficient NSCLC cells but not the cells with wild-type p53 to IR.
"We are glad to find that MCL has an even stronger radiosensitizing effect on NSCLC cells if under hypoxia, it presents radiosensitizing effect through inhibiting hypoxia-inducible factor-1α (HIF-1α)", said HAN Wei.
In fact, HIF-1α is an important negative factor for tumor radiotherapy and the expression and activity of HIF-1α can be enhanced by IR and hypoxia.
The team found that MCL markedly inhibited the expression of HIF-1α after IR and hypoxic exposure in H1299 and Calu-1 (p53-deficient) cells rather than in H460 (p53 wild-type) cells.
Consistently, IR- or hypoxia-induced expression of vascular endothelial growth factor (VEGF), a targeted gene of HIF-1α, was also significantly inhibited by MCL in H1299 and Calu-1 cells, but not in H460 cells.
"MCL inhibites HIF-1α expression via accelerating the degradation of HIF-1α mediated by ubiquitin-proteosome system. In addition, the transfection of wild-type p53 into H1299 cells attenuats the radiosensitizing effect of MCL, suggesting p53's negative role in MCL-mediated radiosensitization in NSCLC cells", said HAN.
Owing to the outstanding effect revealed by this study on enhancing radiosensitivity of p53-deficient NSCLC cells, MCL might be a candidate for an effective radiosensitizer for clinical radiotherapy.
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