An article published in “Biochemical Pharmacology” using our FITC Apoptosis Detection Kit by our customers from the Istituto Nazionale dei Tumori, Italy, in the analysis of how FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models. Congrats and Thanks.
Summary:
The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being
evaluated in multiple clinical trials as an anticancer agent. XPO1
participates in the nuclear export of FoxO-1, which we previously found to be
decreased in platinum-resistant ovarian carcinoma. The aim of this study was to
determine whether enriching FoxO-1 nuclear localization using selinexor would
increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a
single agent, displayed a striking antiproliferative effect in different
ovarian carcinoma cell lines. A schedule-dependent synergistic effect of
selinexor in combination with cisplatin was found in cisplatin-sensitive
IGROV-1, the combination efficacy being more evident in sensitive than in the
resistant cells. In IGROV-1 cells, the combination was more effective when
selinexor followed cisplatin exposure. A modulation of proteins involved in apoptosis (p53, Bax) and in cell cycle progression (p21WAF1) was found by Western blotting. Selinexor-treated cells exhibited
enriched FoxO-1 nuclear staining. Knock-down experiments with RNA interference
indicated that FOXO1-silenced cells displayed a reduced sensitivity to
selinexor. FOXO1 silencing also tended to reduce the efficacy of the drug combination at
selected cisplatin concentrations. Selinexor significantly inhibited tumor
growth, induced FoxO-1 nuclear localization and improved the efficacy of
cisplatin in IGROV-1 xenografts. Taken together, our results support FoxO-1 as
one of the key factors promoting sensitivity towards selinexor and the
synergistic interaction between cisplatin and selinexor in ovarian carcinoma
cells with selected molecular backgrounds, highlighting the need for treatment
regimens tailored to the molecular tumor features.
Reference:
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