The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Summary

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.

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Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

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Early impact of the Patient Protection and Affordable Care Act on insurance among young adults with cancer: Analysis of the dependent insurance provision

BACKGROUND

The Patient Protection and Affordable Care Act (ACA) included provisions to extend dependent health care coverage up to the age of 26 years in 2010. The authors examined the early impact of the ACA (before the implementation of insurance exchanges in 2014) on insurance rates in young adults with cancer, a historically underinsured group.

METHODS

Using National Cancer Institute Surveillance, Epidemiology, and End Results data for 18 cancer registries, the authors examined insurance rates before (pre) (January 2007-September 2010) versus after (post) (October 2010-December 2012) dependent insurance provisions among young adults aged 18 to 29 years when diagnosed with cancer during 2007 through 2012. Using multivariate generalized mixed effect models, the authors conducted difference-in-differences analysis to examine changes in overall and Medicaid insurance after the ACA among young adults who were eligible (those aged 18-25 years) and ineligible (those aged 26-29 years) for policy changes.

RESULTS

Among 39,632 young adult cancer survivors, the authors found an increase in overall insurance rates in those aged 18 to 25 years after the dependent provisions (83.5% for pre-ACA vs 85.4% for post-ACA; P<.01), but not among individuals aged 26 to 29 years (83.4% for pre-ACA vs 82.9% for post-ACA; P = .38). After adjusting for patient sociodemographics and cancer characteristics, the authors found that those aged 18 to 25 years had a 3.1% increase in being insured compared with individuals aged 26 to 29 years (P<.01); however, there were no significant changes noted in Medicaid enrollment (P = .17).

CONCLUSIONS

The findings of the current study identify an increase in insurance rates for young adults aged 18 to 25 years compared with those aged 26 to 29 years (1.9% vs -0.5%) that was not due to increases in Medicaid enrollment, thereby demonstrating a positive impact of the ACA dependent care provisions on insurance rates in this population. Cancer 2016. © 2016 American Cancer Society.

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A phase II, open-label trial of bortezomib (VELCADE ® ) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Abstract

Background

Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin.

Methods

Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m2 i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m2, (days 1 and 8), and cisplatin 70 mg/m2 (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity.

Results

Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3–4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2–4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9–27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %.

Conclusion

The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

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The IL-1 cytokine family and its role in inflammation and fibrosis in the lung

Abstract

The IL-1 cytokine family comprises 11 members (7 ligands with agonist activity, 3 receptor antagonists and 1 anti-inflammatory cytokine) and is recognised as a key mediator of inflammation and fibrosis in multiple tissues including the lung. IL-1 targeted therapies have been successfully employed to treat a range of inflammatory conditions such as rheumatoid arthritis and gouty arthritis. This review will introduce the members of the IL-1 cytokine family, briefly discuss the cellular origins and cellular targets and provide an overview of the role of these molecules in inflammation and fibrosis in the lung.

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Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia

Abstract

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.

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Pearls & Oy-sters: Symptomatic innominate artery disease

A 64-year-old man presented to the emergency department with left-sided weakness and speech impairment upon awakening. He had a history of multiple myocardial infarctions and had undergone coronary angioplasty and coronary artery bypass graft surgery 1 year previously. He was a heavy smoker and had arterial hypertension. He was taking aspirin 100 mg QD, clopidogrel 75 mg QD, simvastatin 40 mg QD, and enalapril 5 mg BID.

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