Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

Abstract

FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. We previously showed that restoration of FUS1 function in 3p21.3-deficient human non-small-cell lung cancer (NSCLC) cells significantly inhibited tumor cell growth in vitro and in vivo. In this study, we evaluated the combined effects of the tumor suppressor FUS1 and the chemotherapeutic drug cisplatin on tumor cell growth and apoptosis induction in NSCLC cells, and explored the molecular mechanism of their mutual action. Exogenous expression of FUS1 by nanoparticle-mediated gene transfer sensitized the response of NSCLC cells to cisplatin, resulting in a 4-to 6-fold increase in tumor-suppressing activity. A systemic treatment with a combination of FUS1-nanoparticles and cisplatin in a human H322 lung cancer orthotopic xenograft mouse model dramatically enhanced the therapeutic efficacy of cisplatin. We also found that the FUS1-enhanced chemosensitivity is associated with the downregulation of MDM2, accumulation of p53 and activation of the Apaf-1-dependent apoptosis pathway. Our results demonstrated an important role of FUS1 in modulating chemosensitivity of lung cancer cells, and suggested that a proper combination of molecular therapeutics such as the proapoptotic tumor suppressor FUS1 and the conventional chemotherapeutic drugs such as cisplatin may be an efficient treatment strategy for human lung cancer.

In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection

“…6,9,35,36 We inoculated NCI-H69 cells subcutaneously (s.c.) on the flanks of NMRI nude mice for testing of the ability of the DOTAP/chol lipoplexes to facilitate gene expression in SCLC s.c. xenografts. The tumors reached approximately 200-500 mm 3 in size when the experiment was started.…”

IL-24 gene transfer sensitizes melanoma cells to erlotinib through modulation of the Apaf-1 and Akt signaling pathways

“…Apoptosis was measured by flow cytometry using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) or a prodidium iodide (PI) staining-based fluorescence-activated cell sorter (FACS) as described previously [51, 52]. In brief, melanoma cell lines plated in 6-well plates (200,000 cells/well) were co-treated with Ad-IL-24 vector (2000 vp/cell) and erlotinib at the IC 20 dose.…”

“…To date, most of the current efforts for melanoma treatment have focused on mitogen-activated protein kinase (MAPK) inhibitors or immunotherapy approaches [43-45], and the erlotinib-mediated EGFR-targeted therapy has not been tested in melanoma. Based on the findings that EGFR-associated PTK signaling pathway is involved in melanoma tumorigenesis [46-51] and that IL-24 can induce apoptosis and inhibit EGFR-associated PTK cell survival signaling pathway [13-19, 43], we hypothesize that an integrated treatment by combining the IL-24-mediated molecular therapy and the erlotinib-mediated EGFR-targeted therapy can increase the inhibition of melanoma growth and enhance the sensitivities of melanoma cells to erlotinib treatment. In this study, we evaluated the combined effect of IL-24 gene transfer and erlotinib on cell growth inhibition and apoptosis induction in various melanoma cells and examined their mutual mechanisms of action for melanoma suppression.…”

How can nanomedicines overcome cellular-based anticancer drug resistance?

“…262 Another approach consisted in using nanoparticles for the co-delivery of anticancer agents and epigenetic drugs, the latter being capable of inducing reactive expression of tumor suppressor genes, thereby enhancing the anticancer activity of the chemotherapeutic agent. 280,281 In contrast to p53, Bcl-2 is an anti-apoptotic gene which acts by preventing the release of cytochrome C from mitochondria, thus protecting the cancer cells from the apoptotic effect that results from a variety of stimuli. The strong upregulation of Bcl-2 in resistant cell lines confirms the role of this gene in the development of resistance to anticancer agents, which could also arise from repeated anticancer treatment (acquired resistance).…”