Combined Effects of p53 Gene Therapy and Leptomycin B in Human Esophageal Squamous Cell Carcinoma

Abstract

Background: p53 gene therapy has been examined in several clinical trials, however, the results of those trials have mostly been unsatisfactory due to the low efficacy of this therapy. Leptomycin B (LMB) is an antibiotic originally isolated from Streptomyces that has the ability to inhibit the export of proteins containing a nuclear export signal from the nucleus to the cytoplasm. Currently, it has been shown that p53 protein has a nuclear export signal. In this study, we assessed whether LMB augments the transduced p53 gene effect. Methods: Antiproliferative effect of LMB was assessed in human esophageal squamous cancer cell lines. Accumulation of p53 protein into the nucleus by LMB was observed by fluorescence microscopy. The combined effect of p53 and LMB was evaluated in in vitro experiments. Results: LMB induced cell death in a dose-dependent manner and p53 drastically accumulated in the nucleus after LMB treatment. The combinatory treatment of p53 gene and LMB significantly increases the efficiency compared to either agent alone. Conclusions: Our findings suggest that LMB has a potent ability to augment the effect of the tumor suppressor p53 in esophageal squamous cancer cell lines and that it is a promising component in p53 gene therapy.

KPT-330 has antitumour activity against non-small cell lung cancer

“…p53 is mutated in more than half of all human cancers, leading to a variety of biological effects and often associated with a poor clinical outcome (Freedman and Levine, 1998; Lecane et al , 2003; Hoshino et al , 2008). Nuclear export of this protein is mediated exclusively through CRM1 (Stommel et al , 1999).…”

“…The presence of p53 mutations is a poor prognostic marker in patients with adenocarcinoma of the lung (Stewart, 2010). Previously, LMB was shown to induce cell death in cervical carcinoma cell lines; these cells likely expressed papilloma virus E6 associated with inactivation of p53 (Freedman and Levine, 1998; Lecane et al , 2003; Hoshino et al , 2008). The potential of a CRM1 inhibitor as a therapeutic agent against lung cancer including those with p53 alterations has not been fully investigated.…”

Differential Interactions of Falcarinol Combined with Anti-Tumour Agents on Cellular Proliferation and Apoptosis in Human Lymphoid Leukaemia Cell Lines

“…Leptomycin B is known to induce apoptosis through blocking CRM-1 mediated nuclear exports leading to accumulation of pro-apoptotic proteins such as p53, FOXO transcription factors and HSP 27 within the nucleus [44,59]. In 2006, a study showed synergistic actions of Leptomycin B with the ABL kinase inhibitor Imatinib Mesylate [46].…”

“…Leptomycin B (LMB) is a nuclear export inhibitor, which prevents protein transfer from the nucleus to the cytoplasm through nuclear pores leading to accumulation of proteins within the nucleus such as p53 and NFκB leading to modulation of apoptotic signalling [44,45]. LMB acts synergistically with a number of anti-cancer agents such as ABL kinase inhibitor: Imatinib mesylate by excluding BCR/ABL from the cytosol leading to accumulation of death signals in the nucleus of CML cells [46].…”

Electrotherapy, a recent mode for anticancer treatment

“…Actually, several developments for alternative therapeutic procedures have been done for this disease, which are mainly used as adjuvants of traditional ones. Among others can be mentioned: gene therapy [8] and antiangiogenic procedures [9], anticancer vaccines [10], treatments using ascorbic acid megadoses [11], hyperthermia [12], electrochemotherapy [13], and electrotherapy or electrochemical therapy [14,15]. Electrotherapy involves the application of a continuous electric low intensity direct current, LIDC, using at least two electrodes which fall within the tumour and/or around it [14][15][16][17].…”