Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells

Abstract

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.

RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

“…RAD51 may interact and regulate the protein stability of HIF1α, especially under genotoxic conditions, leading to enhanced glycolysis and contributing to chemotherapy and radiotherapy resistance [35]. HIF1α protein stabilization and upregulation is regarded as an important factor in chemotherapy and radiotherapy resistance in pancreatic cancer [35, 36]. The present study may shed light on approaches to prevent chemotherapy and radiotherapy resistance in pancreatic cancer by targeting the RAD51/HIF1α axis.…”

Mxd1 mediates hypoxia‐induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene

“…The hypoxic tumor micro‐environment is an important factor for drug resistance development . Hypoxia‐induced chemoresistance to commonly used chemotherapeutic drugs, such as cisplatin (CDDP), doxorubicin, 5‐flouoruracil, and docetaxel has been previously reported in a number of tumor cell types . Although different approaches are continuously being developed in an effort to circumvent hypoxia‐induced chemoresistance, the outcomes have been limited.…”

“…5,33 Hypoxia-induced chemoresistance to commonly used chemotherapeutic drugs, such as cisplatin (CDDP), doxorubicin, 5-flouoruracil, and docetaxel has been previously reported in a number of tumor cell types. 9,18,34,35 Although different approaches are continuously being developed in an effort to circumvent hypoxia-induced chemoresistance, the outcomes have been limited. In the present study, we addressed this hurdle of hypoxia-induced drug resistance in osteosarcoma cells by using CDDP.…”

Synergistic antitumor effects of histone deacetylase inhibitor scriptaid and bortezomib against ovarian cancer cells

“…In the present study, we investigated the antitumor effects of scriptaid, used either alone or in combination with bortezomib, as well as with standard chemotherapeutics: paclitaxel, doxorubicin, carboplatin or etoposide, on representative ovarian cancer cells in vitro. The rationale for combining scriptaid together with bortezomib or with conventional chemotherapeutics was that the former can sensitize ovarian cancer cells and can reverse resistance of cancer cells to drugs used in currently established therapeutic protocols (26)(27)(28)(29). 2 tissue flasks (nunc, roskdile, Denmark) at 37˚C in a humidified atmosphere of 5% CO 2 and were passaged two to three times weekly.…”