Enhanced radiosensitivity of non-small-cell lung cancer (NSCLC) by adenovirus-mediated ING4 gene therapy

Abstract

Radiotherapy is the common treatment of choice for locally advanced lung cancer, but the radioresistance of lung cancer remains a significant therapeutic obstacle. We previously demonstrated that adenovirus-mediated inhibitor of growth 4 (ING4) tumor suppressor gene delivery (AdVING4) can chemosensitize human hepatocarcinoma cells to anticancer drug cisplatin (CDDP). However, its radiosensitizing effects in cancer therapy are largely elusive. In the present study, we investigated the therapeutic efficacy of AdVING4 gene therapy combined with ionizing radiotherapy for SPC-A1 human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo in athymic nude mice, and also elucidated its underlying mechanisms. We found that AdVING4 gene therapy plus radiotherapy induced synergistic tumor suppression and apoptosis in in vitro SPC-A1 human NSCLC cells and in vivo SPC-A1 xenografted tumors s.c. implanted in athymic nude mice. Mechanistically, AdVING4 combined with radiation resulted in a substantial upregulation of Bax, Fas, FasL and Cleaved Caspase-3, and downregulation of Bcl-2 in SPC-A1 human NSCLC xenografted tumors. In addition, AdVING4 plus radiation synergistically reduced the tumor vessel CD34 expression and microvessel density (MVD) in vivo. Most importantly, AdVING4 potentially blocked the radiation-induced enhancement of cyclooxygenase-2 and survivin radioresistant factors, and vascular endothelial growth factor and IL-8 proangiogenic factors. The enhanced antitumor effects elicited by AdVING4 plus radiotherapy were closely associated with the cooperative activation of intrinsic and extrinsic apoptotic pathways, and synergistic inhibition of tumor angiogenesis. Thus, our results suggested that AdVING4 combined with radiotherapy may be a feasible and effective strategy for treatment of radioresistant NSCLC and other cancers.

Adenovirus-mediated ING4 expression reduces multidrug resistance of human gastric carcinoma cells in vitro and in vivo

“…ING4 has been reported to enhance chemosensitivity to DNA-damage agents, such as doxorubicin or etoposide in human hepatocarcinoma cells (19,26). Our previous data also demonstrated that adenovirus-mediated (AdVING4) gene therapy sensitized human hepatocarcinoma cells to cisplatin (CDDP) and enhanced the radiosensitivity of non-small-cell lung cancer (19,25). However, reversal of its resistance in human cancers has not been reported.…”

“…Moreover, restoration of ING4 expression was found to suppress tumor growth in a p53-dependent and p53-independent manner, induce tumor cell cycle arrest and apoptosis (13,(19)(20)(21), and inhibit tumor angiogenesis by repressing nuclear factor-κB and hypoxia-inducible factor-1α (22)(23)(24). ING4 protein can also enhance radiosensitivity and chemosensitivity in nonsmall-cell lung cancer and hepatocarcinoma cells (19,25). In the present study, we first successfully established the CDDPinduced MDR phenotype in a gastric carcinoma cell line for assessing the effects of the AdVING4 gene on the reversion of the MDR phenotype in gastric carcinoma cells in vitro and in vivo.…”

“…Recently, cancer gene therapy represents a promising novel therapeutic modality for cancers, particularly for the treatment of cancers of the digestive system (31). Various strategies combining gene or molecular therapy with chemotherapy have been applied to radiosensitize or chemosensitize tumor cells to chemotherapy or radiation therapy and to reduce treatment-associated toxicity (25,26,32). To date limited success has been reported.…”

“…A previous study showed that apoptosis-related genes (such as Bax, Bcl-2 and survivin) are key factors responsible for MDR (25,32,46). The ratio of anti-to pro-apoptotic Bcl-2 family molecules, such as Bcl-2/Bax, constitutes a rheostat that sets the threshold of susceptibility to apoptosis for the intrinsic apoptosis pathway, which promotes pore formation in the mitochondrial outer membrane, loss of mitochondrial integrity, and the release into the cytosol of cytochrome c followed by the cleavage of caspase-9, leading to the activation of the intrinsic apoptotic pathway.…”

“…In addition, the ING4-dominant mutant can promote MYC-initiated mouse mammary carcinogenesis (18), whereas overexpression of ING4 protein can apparently enhance tumor growth inhibition in a p53-dependent and p53-independent manner by induction of cell cycle alteration and apoptosis (13,(19)(20)(21) and inhibition of tumor angiogenesis by repressing nuclear factor κB and hypoxia-inducible factor-1α (22)(23)(24). In addition, ING4 can enhance radiosensitivity and chemosensitivity in non-small cell lung cancer SPC-A1 cells and hepatocarcinoma cells, respectively (19,25). Previous studies have shown that the combination of radiotherapy, chemotherapy, and other conventional therapies with gene therapy is a promising practice for the treatment of cancers (26)(27)(28).…”