Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin

Our plain-English summary of Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin, by M. De Cesare, D. Cominetti, V. Doldi, et al (Oncotarget, 2015).

The study

• Authors: M. De Cesare, D. Cominetti, V. Doldi, A. Lopergolo, M. Deraco, P. Gandellini, S. Friedlander, Y. Landesman, M.G. Kauffman, S. Shacham, M. Pennati, N. Zaffaroni
• Journal: Oncotarget
• Published: 2015;6(15):13119-32
• Cited by: 39 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM.

In plain English

This laboratory study tested three experimental drugs (KPT-251, KPT-276 and selinexor) against diffuse malignant peritoneal mesothelioma, a cancer of the abdominal lining. It did not study asbestos exposure. The authors used two human tumor cell lines (STO and MesoII), grown from surgical specimens of patients in Milan, and mice implanted with these tumors. In laboratory dishes, the drugs slowed tumor cell growth and triggered cell death. They did not alter the growth of two normal human cell lines at concentrations up to 10 μmol/L. The drugs shifted where the survival-promoting protein survivin sat inside cells, and survivin levels then fell. In mice with early-stage STO tumors under the skin, oral KPT-251 and KPT-276 each reduced tumor volume by up to 84% compared with mice given only the drug vehicle. In mice with tumors inside the abdomen, average tumor weight was 88 mg with selinexor versus 328 mg in vehicle-treated controls. The authors reported no toxic deaths and weight loss under 5%. Adding YM155 to selinexor boosted effects in dishes but did not appreciably improve selinexor's effect in mice with early-stage STO tumors. The authors suggested these drugs as a possible new treatment option.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: experiments on human tumor cell lines (in vitro) and on mice carrying implanted human tumors (animal experiment)
• Who was studied: Two human diffuse malignant peritoneal mesothelioma cell lines (STO, with wild-type TP53, and MesoII, with mutant TP53), established from surgical specimens of patients operated at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Two normal human cell lines (WI38 lung fibroblasts, RWPE-1 prostate) were used for comparison. Nude mice with tumors under the skin (eight mice per group). SCID mice with STO cells injected into the abdomen (nine mice per group).
• Exposure: No asbestos exposure was studied. The exposures were the drugs KPT-251, KPT-276 and selinexor (KPT-330), alone or combined with the survivin inhibitor YM155. In mice, the drugs were given by mouth: KPT-251 at 50 mg/kg twice a week for 4 weeks, KPT-276 at 50 mg/kg 5 days a week for 3 weeks, and selinexor at 10 mg/kg twice a week for 4 weeks. Control mice received the drug vehicle.
• Main results:
  • In STO cells, the concentration that halved cell growth (IC50) was 0.07 μmol/L for selinexor, 0.23 for KPT-251 and 0.24 for KPT-276. In MesoII cells, IC50 values ranged from 0.35 to 0.47 μmol/L across the three drugs.
  • At concentrations up to 10 μmol/L, the drugs did not alter the growth of the normal lung fibroblast (WI38) or prostate (RWPE-1) cell lines.
  • After 72 hours at the higher dose (IC80), activity of the cell-death enzyme caspase-3 was 7-, 6- and 11-fold higher than in untreated controls in STO cells (KPT-251, KPT-276, selinexor). In MesoII cells it was 21-, 23- and 33-fold higher.
  • The drugs caused survivin to build up in the cell nucleus and fall in the cytoplasm. From 12 hours, nuclear survivin then decreased through tagging for breakdown (ubiquitination), and survivin mRNA was not affected.
  • In cells, the drugs combined with YM155 inhibited growth more than expected from adding their separate effects. In mice, the combination was tested only in early-stage STO tumors, where YM155 did not appreciably improve selinexor's effect.
  • In mice with early-stage STO tumors under the skin, maximum tumor volume inhibition versus vehicle-treated controls was 84% (KPT-251), 84% (KPT-276) and 79% (selinexor). With selinexor it was 54% in late-stage STO tumors, 68% in early-stage MesoII tumors and 62% in late-stage MesoII tumors.
  • In SCID mice with STO tumors inside the abdomen, average tumor burden was 328 mg in vehicle-treated controls and 88 mg in selinexor-treated mice (73% inhibition).
  • The drugs were well tolerated in mice, with no toxic deaths and weight loss below 5%.
• The authors' conclusion: The authors concluded that their preclinical data could support clinical testing of these drugs for diffuse malignant peritoneal mesothelioma. They said that lowering survivin appears to be a main way the drugs act in these models.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Apoptosis.

Related studies

• Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma — N. Zaffaroni, A. Costa, et al. (2007)
• BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients — J. Hmeljak, N. Erčulj, et al. (2011)
• CpG-oligodeoxynucleotides exert remarkable antitumor activity against diffuse malignant peritoneal mesothelioma orthotopic xenografts — M. De Cesare, L. Sfondrini, et al. (2016)
• Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research — D. Baratti, S. Kusamura, et al. (2011)
• Preclinical development of HIvax: Human survivin highly immunogenic vaccines — P.R. Hoffmann, M. Panigada, et al. (2015)
• miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma — R. El Bezawy, S. Percio, et al. (2022)

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