Non-small cell lung cancer (NSCLC), comprising 85% of
lung cancer cases, has been associated with resistance to chemo/
radiotherapy. The hypoxic
tumor micro-environment, where insufficient vasculature results in poor
drug penetrance and sub-optimal
chemotherapy in the
tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of
therapy. In our study, we have investigated the effectiveness of a combination of
cisplatin with
scriptaid [a pan-
Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of
hypoxia and sub-lethal
chemotherapy.
Scriptaid synergistically increases the efficacy of
cisplatin in normoxia as well as
hypoxia, accompanied with reduced
metastasis and enhanced DNA damage. Addition of
scriptaid also overcomes the
cisplatin resistance exhibited in
lung cancer cells with stabilized
hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and
hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose
cisplatin and
scriptaid is cytotoxic to NSCLC lines, can overcome
hypoxia induced resistance and mutant p53- induced instability often associated with this
cancer, and has the potential to be an effective therapeutic modality.