Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells

Abstract

ING4 as a member of inhibitor of growth (ING) tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24), a cytokine-tumor suppressor, also shows broad-spectrum and tumor-specific antitumor activities. In this report, we constructed an ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) and assessed its combined effect on in vitro and in vivo A549 human non-small cell lung cancer cells. We demonstrated that ING4 and IL-24 combination treatment by adenovirusmediated ING4 and IL-24 coexpression induced additive growth suppression and apoptosis as well as an overlapping effect on upregulation of P21, P27, Fas, Bax and cleaved Caspases-8, 9, 3 and downregulation of Bcl-2 in in vitro A549 lung carcinoma cells. Moreover, Ad-ING4-IL-24 treatment additively inhibited in vivo A549 lung carcinoma subcutaneous (s.c.) xenografted tumor growth and reduced CD34 and microvessel density in A549 xenografted tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the coordinate activation of extrinsic and intrinsic apoptotic pathways and additive inhibition of tumor angiogenesis. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for lung carcinoma and other cancers.

ING1 and 5-Azacytidine Act Synergistically to Block Breast Cancer Cell Growth

“…Several of the ING proteins can inhibit the growth of cancer cells in vitro and in vivo when overexpressed using adenoviral vectors [23], [24], [25], [26], [27], [28]. The ING proteins might be particularly useful to enhance chemosensitivity in combination with agents like etoposide and doxorubicin [29].…”

Non‐viral nucleic acid delivery to the central nervous system and brain tumors

“…These findings revealed that ING4 may attenuate the growth of various tumors. Numerous studies have shown that cancers such as brain tumors, gastric carcinoma, lung cancer, head and neck squamous cell carcinoma, malignant melanoma, hepatocellular carcinoma and ovarian carcinoma could be inhibited by ING4 as a result of its multimodal tumor suppressive ability. In addition, ING4 can enhance the sensitivity of various cancer cells to chemotherapeutic agents, such as doxorubicin and etoposide.…”

The Emerging Role of Inhibitor of Growth 4 as a Tumor Suppressor in Multiple Human Cancers

“…Extensive studies have shown that IL-24 displays ubiquitous antitumor property and tumor-specific killing activity [97]. ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) combination treatment was shown to have a synergistic tumor-suppressive capacity in NSCLC, breast cancer and hepatocarcinoma and promote radiosensitivity of breast cancer cells [98][99][100][101]. …”