Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma

Zhang, Kejie; Wang, Michael; Tamayo, Archito T.; Shacham, Sharon; Kauffman, Michael; Lee, John; Zhang, Liang; Ou, Zhishuo; Li, Changping; Sun, Lejia; Ford, R.; Pham, Lan V.

doi:10.1016/j.exphem.2012.09.002

Cited by 93 publications

(127 citation statements)

References 46 publications

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“…Correlation between CRM-1 and survivin expression in the nucleus and cytoplasm in gastric and colorectal carcinoma. family are novel therapeutic targets in renal cell carcinoma, non-small cell lung carcinoma and lymphoma (19,(34)(35)(36). The present study compared CRM-1 expression in gastric and colorectal carcinomas.…”

Section: Crm-1 Expression -------------------------------------------mentioning

confidence: 90%

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

et al. 2016

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Abstract. Survivin, a member of the inhibitor of apoptosis protein family, is a potential prognostic marker and molecular target for anticancer therapies. Chromosomal regional maintenance protein-1 (CRM-1) mediates the nuclear export of proteins such as survivin. The aims of the present study were to compare the expression and subcellular localization of CRM-1 in human gastric and colorectal carcinomas and to assess the association between CRM-1 and survivin expression in these tumor types. The nuclear and cytoplasmic CRM-1 expression rates in gastric carcinoma were 61% (42/69) and 29% (20/69), respectively, while the nuclear and cytoplasmic CRM-1 expression rates in colorectal carcinoma were 55% (43/78) and 37% (29/78), respectively. Nuclear and cytoplasmic CRM-1 expression was found to be significantly correlated with nuclear and cytoplasmic survivin expression in colorectal carcinoma, but not gastric carcinoma. These results indicate that CRM-1 expression patterns differ between gastric and colorectal carcinomas and thus, we hypothesize that CRM-1-mediated nuclear export of survivin may be deregulated in gastric carcinoma. Therefore, CRM-1 may exhibit different functions in gastric and colorectal carcinoma.

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Section: Crm-1 Expression -------------------------------------------mentioning

confidence: 90%

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

et al. 2016

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“…KPT-185 and KPT-276 were found to be associated with significant increase in the apoptosis in MCL cell lines and mouse models in a p53 dependent as well as p53 independent manner. Also, it was observed that these drugs downregulated c-myc and NFκB [46,47] . Sequencing of PMBL samples showed recurrent hot-mutation (E571K) of XPO1.…”

Section: Role Of Selective Inhibitors Of Nuclear Export (Xpo1 Inhibitmentioning

confidence: 99%

“…Recent studies showed that XPO1 highly expressed in MCL patients samples than normal B-cell controls [46,47] . KPT-185 and KPT-276 were found to be associated with significant increase in the apoptosis in MCL cell lines and mouse models in a p53 dependent as well as p53 independent manner.…”

Section: Role Of Selective Inhibitors Of Nuclear Export (Xpo1 Inhibitmentioning

confidence: 99%

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

Sneha¹,

P²,

Bindhya³

et al. 2017

Can Cell Microenviron

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Cancer is one of the leading cause of morbidity and mortality worldwide. Regulated nucleo-cytoplasmic shuttling is very crucial for maintaining cellular homeostasis. Emerging evidence suggests that deregulation of the nucleo-cytoplasmic transport results in abnormal cell growth, cell cycle, apoptosis, tumor progression and drug resistance. Exportin-1 (also called as chromosome region maintenance 1) belongs to karyopherin-β superfamily and is the main mediator of nuclear export in several cell types. The XPO1/CRM1 protein is overexpressed in liposarcoma, Ewing sarcoma, ovarian carcinoma, pancreatic cancer, hepatocellular carcinoma, lung carcinoma, osteosarcoma, gastric carcinoma, melanoma, glioma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid/lymphoid leukemia as well as multiple myeloma. Hot spot mutations were observed in many cancers. Higher levels of XPO1/CRM1 are associated with poor prognosis, resistance to chemotherapy and recurrence in a large number of human malignancies. There are growing evidence that provided the foundation that inhibition of nuclear export by inhibiting nuclear export receptor (XPO1) might be a potential targeted therapeutic approach for the treatment of human cancers in the clinic. In the present review, we will discuss the role of XPO1 in cancers and potential of selective inhibitors of nuclear export (XPO1 inhibitors) to restore the normal function of tumor suppressor and growth regulatory proteins by blocking their export. Selinexor (KPT-330) is an orally available, highly potent and is being tested in human phase-I/II clinical trials in both haematological and solid malignancies.

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“…Another naphthol derivative has been synthesized and it is found that it is a cell-permeable small molecule inhibitor of KIX-KID interaction, an essential interaction for CREBdependent gene transcription activation. As a result, this compound is able to inhibit CREB-mediated gene transcription in living cells [11]. Figure 1 showed the basic structural requirements (pharmacophoric features) of histone deacetylase 1 inhibitors; i) Surface recognition Group, ii) Linker group, iii) metal binding group [12].…”

Section: Experimental Chemistrymentioning

confidence: 99%

Design, Synthesis, Molecular Modelling and Biological Evaluation of Novel α-Naphtholhydroxamate Derivatives as Potential Anticancer Agents

Abdelrahim¹,

Mohan²,

Albarrati³

et al. 2016

Med chem (Los Angeles)

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Chemotherapy is one of the treatment options for cancer. A major problem in cancer chemotherapy is the lack of selective toxicity of many commonly used anti-cancer agents towards tumor tissue compared to normal tissue. Studies have shown that α-naphthol is selectively toxic to cultures of human tumor tissue compared to normal tissues in vitro. Hence, this study was conducted to synthesize a series of new hydroxamate derivatives containing α-naphthol nucleus by the reaction of naphthol acetic acid with amino acid methyl ester derivatives which were directly reacted with hydroxyl amine at room temperature. Structures of these compounds were confirmed by standard studies of IR, 1 H NMR, 13 CNMR, MS and elemental analysis. The cytotoxicity of the synthesized compounds were studied using the MTT assay in four human cancer cell lines, including HepG2, PC-3, HT-29 and MCF-7. Among the compounds, compound 6 g and 6 h exhibited a significant cytotoxicity against almost all the used cells including the normal cells . Further studies have shown that the cell death observed was closely associated with generation of reactive oxygen species (ROS). In this study, other naphthol derivatives have shown significant increase in the level of ROS in concentration dependent manner in treated cells. In conclusion, the study has shown that among the synthesized compounds, compounds 6 g , 6 k and 6 h hold the potential for further research. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, HDAC (PDB-code: 1T69).

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Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma

Cited by 93 publications

References 46 publications

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

Design, Synthesis, Molecular Modelling and Biological Evaluation of Novel α-Naphtholhydroxamate Derivatives as Potential Anticancer Agents

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