Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin

Garg, Manoj; Kanojia, Deepika; Mayakonda, Anand; Ganesan, Trivadi S.; Bindhya, S.; Suresh, Sidhanth; Sneha, Smarakan; Nagare, Rohit P.; Said, Jonathan; Doan, Ngan; Ding, Ling-Wen; Baloglu, Erkan; Shacham, Sharon; Kauffman, Michael; Koeffler, H. Phillip

doi:10.1038/s41598-017-10325-x

Cited by 35 publications

(17 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SINE compounds, generally, cause nuclear accumulation of tumor suppressors and cell cycle inhibitors and sensitize resistant cancer cells to other drugs. The anti-cancer activity of SINE compounds in combination with standard therapies achieves high remission rates and has been highlighted by different studies [ 106 , 107 , 108 , 109 ]. For example, in multiple triple-negative breast cancer (TNBC) models, antitumor efficacy of Selinexor increased in combination with paclitaxel or eribulin [ 110 ].…”

Section: Targeting Nucleocytoplasmic Transportmentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

View full text Add to dashboard Cite

Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors.

show abstract

Section: Targeting Nucleocytoplasmic Transportmentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

View full text Add to dashboard Cite

show abstract

“…ROS have been targeted by a number of anticancer drugs. Antitumor drugs anthracyclines and topoisomerase inhibitors such as doxorubicin, adriamycin, daunorubicin, and epirubicin can block DNA synthesis, topoisomerase II activity and complex I/II and increase mitochondrial ROS production to kill tumor cells [14,15]. Platinum-based drugs including cisplatin, carboplatin and oxaliplatin also can induce tumor cell death by maintaining very high levels of ROS [16,17].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer

Cao

Wang

Tian

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background: Gastric cancer (GC) is a common form of malignant cancer in worldwide which has a poor prognosis. Despite recent improvements in the treatment of GC, the prognosis is not yet satisfactory for GC patients. CYT997, a novel microtubule-targeting agent, recently has been identified to be a promising anticancer candidate for the treatment of cancers; however, the effects of CYT997 in GC remain largely unknown. Methods: Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry. The mitochondrial ROS were detected by confocal microscope and flow cytometry. Gastric cancer patient-derived xenograft (PDX) model was used to evaluate its antitumor activity of CYT997 in vivo. Results: CYT997 inhibited gastric cancer cell proliferation and induced cell apoptosis and triggered autophagy. CYT997 induced apoptosis through triggering intracellular mitochondrial ROS generation in GC cells. ROS scavengers N-acetylcysteine (NAC) and Mitoquinone (MitoQ) distinctly weakened CYT997-induced cell cycle G2/M arrest and apoptosis in GC cells. Pretreatment with autophagy inhibitor 3-MA promoted the effect of CYT997 on cells apoptosis. Mechanistically, CYT997 performed its function through regulation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in GC cells. In addition, CYT997 inhibited growth of gastric cancer patient-derived xenograft (PDX) tumors. Conclusions: CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC.

show abstract

“…As these side effects are partly dose-dependent, a reduction in the ADM dose without reducing its therapeutic effect would therefore be of high clinical value. Therapeutic results could be improved if cancer cells were killed by ADM combined with a ‘chemotherapy sensitizer’ (18).…”

Section: Discussionmentioning

confidence: 99%

1,25‑dihydroxyvitamin D3 enhances the susceptibility of anaplastic thyroid cancer cells to adriamycin‑induced apoptosis by increasing the generation of reactive oxygen species

Zhang

Sun

et al. 2019

Mol Med Report

View full text Add to dashboard Cite

Anaplastic thyroid cancer (ATC) is a very aggressive malignancy that is resistant to various types of chemotherapy in humans. Most patients with late-stage ATC cannot undergo surgery and receive chemotherapy drugs. The present study investigated the influence of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) pretreatment on adriamycin (ADM) chemotherapy efficacy in the 8305c and 8505c ATC cell lines. The apoptotic effects of ADM on ATC cells pretreated with 1,25(OH) 2 D 3 were evaluated. Cell viability was identified by using the Cell Counting Kit-8 assay. Apoptosis was assessed by flow cytometry and staining with Hoechst 33342. The expression of the apoptotic protein cleaved caspase-3 was tested with a colorimetric assay kit and by western blotting. Reactive oxygen species (ROS) generation was assessed with the antioxidant N-acetyl-L-cysteine (NAC) and the assay H 2 -DCFDA. In addition, ROS production could be reversed by NAC treatment. The present study demonstrated that 1,25(OH) 2 D 3 enhanced ADM-induced apoptosis in 8305c and 8505c cell lines. Furthermore, 1,25(OH) 2 D 3 improved the ADM-induced ROS production and expression of cleaved caspase-3. NAC treatment inhibited the expression of cleaved caspase-3 in ATC cells, and reduced apoptosis in cells that were pretreated with 1,25(OH) 2 D 3 and ADM. These results demonstrated that 1,25(OH) 2 D 3 may enhance ADM-induced apoptosis by increasing ROS generation in ATC cells.

show abstract

Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin

Cited by 35 publications

References 50 publications

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer

1,25‑dihydroxyvitamin D3 enhances the susceptibility of anaplastic thyroid cancer cells to adriamycin‑induced apoptosis by increasing the generation of reactive oxygen species

Contact Info

Product

Resources

About