Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• Nuclear factor-kappa B (NF-κB) is a key regulator of cellular responses to radiation.
• Inhibiting NF-κB may sensitize cancer cells to radiation therapy.
• Understanding the role of NF-κB in DNA repair is crucial for improving radiotherapy efficacy.

Purpose of the Study:

• To investigate the efficacy of dimethylaminoparthenolide (DMAPT) in sensitizing human lung cancer cells to X-ray therapy.
• To elucidate the mechanism by which DMAPT enhances X-ray-induced cell killing, focusing on NF-κB inhibition and DNA double-strand break (DSB) repair.
• To evaluate the in vivo efficacy of DMAPT in combination with X-ray therapy.

Main Methods:

• In vitro studies using human lung cancer cell lines treated with DMAPT and X-rays.
• Assessment of NF-κB binding activity using electrophoretic mobility shift assays.
• Analysis of DNA double-strand break (DSB) repair using neutral DNA comet assays.
• In vivo studies using A549 tumor xenografts in nude mice.

Main Results:

• DMAPT decreased cell viability and inhibited both constitutive and radiation-induced NF-κB activity.
• DMAPT enhanced X-ray-induced cell killing in vitro, with dose modification factors of 1.8 and 1.4.
• DMAPT inhibited split-dose recovery and altered the kinetics of X-ray-induced DNA DSB repair.
• Knockdown of p65, an NF-κB family member, mimicked DMAPT's effects on radiosensitivity and DNA repair.
• DMAPT treatment led to enhanced X-ray-induced tumor growth delay in vivo.

Conclusions:

• DMAPT effectively sensitizes human lung cancer cells to X-ray therapy both in vitro and in vivo.
• The mechanism involves the inhibition of NF-κB signaling and subsequent impairment of DNA double-strand break repair.
• DMAPT represents a promising therapeutic agent for enhancing the efficacy of radiotherapy in non-small-cell lung cancer.