selinexor and Colorectal-Neoplasms

Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.. To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.. In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.. Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.. In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Topics: Active Transport, Cell Nucleus; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Hydrazines; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Survival Rate; Triazoles

Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1's interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1

Topics: Adenosine Deaminase; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Transformation, Neoplastic; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Hydrazines; Interferon-gamma; Male; Melanoma, Experimental; Mice, Inbred C57BL; Mice, Knockout; Necroptosis; Pyroptosis; Receptor-Interacting Protein Serine-Threonine Kinases; RNA-Binding Proteins; Signal Transduction; Skin Neoplasms; Triazoles

Exportin 1(XPO1), a nuclear exporter protein, has been gaining recognition in cancer progression and treatment. This study aimed to evaluate the association between the overexpression of XPO1 with NF-κB, Ki67 and clinicopathological characteristics in colorectal cancer (CRC) tissue samples and to explore the anti-proliferative effect of KPT-330, as XPO1 inhibitor, in colorectal cancer cell line.. Forty CRC tissue samples were analyzed by immunostaining for the expressions of XPO1, NF-κB and Ki67 and then the anti-proliferative effect of the KPT-330 was also evaluated in HT29 colorectal cancer cell line.. XPO1 overexpression was observed in 52.5% of CRC and significantly apparent with strong intensity in tumor cells compared to the normal adjacent epithelium (P<0.001). Regarding to the histopathological characteristics, the XPO1 overexpression significantly associated with advanced tumor stages (P=0.049) and has great tendency towards moderate/poorly differentiated tumors. Although the XPO1 overexpression was strongly associated with high Ki67 expression (P=0.001), only Ki67 expression showed significant association with tumor size (P=0.012). No significant association was detected between the XPO1 overexpression and NF-κB, while the NF-κB positive expression was significantly associated with lymph node metastasis and Ki67 expression at P=0.027 and P= 0.007, respectively. The in vitro experiments showed a great impact of KPT-330, as XPO1 inhibitor, to inhibit cancer growth in dose and time dependent manner and significantly diminished the colony formation (P<0.001) of HT29 cells- associated with the expression of Ki67 (P<0.001).. XPO1 overexpression and NF-κB expression may serve as potential biomarker associated with CRC pathogenesis and proliferation, while the KPT-330 is effectively inhibited-colon cancer growth in vitro. Further studies considering the prognostication role of XPO1 overexpression in CRC are required.
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Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Colorectal Neoplasms; Exportin 1 Protein; Female; Follow-Up Studies; HT29 Cells; Humans; Hydrazines; Karyopherins; Ki-67 Antigen; Lymphatic Metastasis; Male; Middle Aged; NF-kappa B; Prognosis; Receptors, Cytoplasmic and Nuclear; Triazoles; Young Adult

Although proteasome inhibitors such as bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a monotherapy for solid tumors, including colorectal cancer. We found in this study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of bortezomib on colon cancer cells containing wild-type p53, which underwent G

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Cell Nucleus; Cell Survival; Colorectal Neoplasms; Drug Synergism; HCT116 Cells; HeLa Cells; Humans; Hydrazines; Mice; Proteasome Inhibitors; Triazoles; Tumor Suppressor Protein p53; Ubiquitination; Xenograft Model Antitumor Assays