Selinexor improves the anti-cancer effect of tucidinostat on TP53 wild-type breast cancer

Background XPO1 mediates the nuclear export of several proteins, mainly tumor suppressors. KPT‐330 (Selinexor) is a selective inhibitor of XPO1 that has demonstrated good therapeutic effects in hematologic cancers. Methods We used TCGA and GTEx pan‐cancer database to evaluate XPO1 mRNA expression in various tumors. Cell proliferation assay and colony formation assay were used to analyze the in vitro antitumor effects of XPO1 inhibitor KPT‐330. Western blot was performed to explore the specific mechanisms. Results We found that XPO1 was highly expressed across a range of cancers and associated with poor prognosis in hepatobiliary and pancreatic tumors. We revealed that the XPO1 inhibitor KPT‐330 triggered the nuclear accumulation of the p53 protein and significantly disrupted the proliferation of cholangiocarcinoma cells. Mechanistically, the XPO1 inhibitor, KPT‐330, reduced BIRC6 expression by inhibiting the PI3K/AKT pathway to decrease p53 degradation and improve its stability. Conclusion Therefore, XPO1 may be a potential therapeutic target in cholangiocarcinoma, mediated by its effects on KPT‐330.

show abstract

“…p53 is a carrier protein for XPO1 12,13 . Therefore, we conducted an immunofluorescence assay to clarify p53 status under KPT‐330 treatment.…”

Section: Resultsmentioning

confidence: 99%

“…p53 is a carrier protein for XPO1. 12 , 13 Therefore, we conducted an immunofluorescence assay to clarify p53 status under KPT‐330 treatment. The results showed that XPO1 inhibition by KPT‐330 triggered the accumulation of p53 inside the nucleus (Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation

Zhao

Yang

et al. 2022

Cancer Medicine

View full text Add to dashboard Cite

show abstract

“…Tucidinostat (chidamide), as a Class I HDAC inhibitor, has been shown to inhibit a variety of cancer growth [ 41 , 42 , 43 , 44 , 45 , 46 ]. Therefore, we selected Tucidinostat in our in vitro cell model to assess its effect on uLMS cell growth.…”

Section: Resultsmentioning

confidence: 99%

Targeting Class I Histone Deacetylases in Human Uterine Leiomyosarcoma

Yang

Falahati

Khosh

et al. 2022

Cells

View full text Add to dashboard Cite

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is unknown. Class I histone deacetylases (including HDAC1, 2, 3, and 8) are one of the major classes of the HDAC family and catalyze the removal of acetyl groups from lysine residues in histones and cellular proteins. Class I HDACs exhibit distinct cellular and subcellular expression patterns and are involved in many biological processes and diseases through diverse signaling pathways. However, the link between class I HDACs and uLMS is still being determined. In this study, we assessed the expression panel of Class I HDACs in uLMS and characterized the role and mechanism of class I HDACs in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that HDAC1, 2, and 3 are aberrantly upregulated in uLMS tissues compared to adjacent myometrium. Immunoblot analysis demonstrated that the expression levels of HDAC 1, 2, and 3 exhibited a graded increase from normal and benign to malignant uterine tumor cells. Furthermore, inhibition of HDACs with Class I HDACs inhibitor (Tucidinostat) decreased the uLMS proliferation in a dose-dependent manner. Notably, gene set enrichment analysis of differentially expressed genes (DEGs) revealed that inhibition of HDACs with Tucidinostat altered several critical pathways. Moreover, multiple epigenetic analyses suggested that Tucidinostat may alter the transcriptome via reprogramming the oncogenic epigenome and inducing the changes in microRNA-target interaction in uLMS cells. In the parallel study, we also determined the effect of DL-sulforaphane on the uLMS. Our study demonstrated the relevance of class I HDACs proteins in the pathogenesis of malignant uLMS. Further understanding the role and mechanism of HDACs in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.

show abstract

“…Furthermore, combined treatment with MDM2 inhibitor, nutlin‐2, resulted in synergistic anti‐leukaemic effects in responsive blasts and cell lines 148 . Similarly, MDM2 inhibition enhanced Selinexor cytotoxicity in both neuroblastoma and ovarian cancer cell models and upregulated expression of p53 by HDAC inhibitor, tuconidostat, improved responsiveness of TNBC cell lines to Selinexor in a p53‐dependent manner 150–152 . Conflicting evidence implicating p53 as a predictor of Selinexor sensitivity suggests that differential in vitro and in vivo responsiveness is likely dependent on cancer subtype.…”

Section: Sine Resistancementioning

confidence: 99%

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Newell,

van der Watt,

Leaner

2023

IUBMB Life

View full text Add to dashboard Cite

Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose‐limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

show abstract

Selinexor improves the anti-cancer effect of tucidinostat on TP53 wild-type breast cancer

Cited by 9 publications

References 39 publications

Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation

Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation

Targeting Class I Histone Deacetylases in Human Uterine Leiomyosarcoma

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Contact Info

Product

Resources

About