Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis

Burikhanov, Ravshan; Sviripa, Vitaliy M.; Hebbar, Nikhil; Zhang, Wen; Layton, W. J.; Hamza, Adel; Chen, Zhan; Watt, David S.; Liu, Chunming; Rangnekar, Vivek M.

doi:10.1038/nchembio.1631

Cited by 59 publications

(70 citation statements)

References 26 publications

(39 reference statements)

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“…13,14 To determine if inhibition of vimentin function is important in DLBCL, we examined the effect of another inhibitor of vimentin, Arylquin 1, which is thought to bind vimentin and induce Par-4 dependent apoptosis. 42 We found that cytotoxicity required 10 fold higher concentration of Arylquin 1 in DLBCL than shown in mouse embryonic fibroblasts and PC-3 cells (data not shown). 42 These results suggest that WA inhibition of vimentin is not likely to be the primary reason for decrease in Akt and apoptosis of DLBCL.…”

Section: Discussionmentioning

confidence: 92%

“…42 We found that cytotoxicity required 10 fold higher concentration of Arylquin 1 in DLBCL than shown in mouse embryonic fibroblasts and PC-3 cells (data not shown). 42 These results suggest that WA inhibition of vimentin is not likely to be the primary reason for decrease in Akt and apoptosis of DLBCL. We suggest that the reduced protein levels of Akt are a result of decreased Hsp90 function as Akt is a confirmed client protein of the Hsp90/cdc37 chaperone complex.…”

Section: Discussionmentioning

confidence: 92%

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Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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Abbreviations: WA, Withaferin A; DLBCL, Diffuse large B cell lymphoma.Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-kB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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“…Studies reveal that primary melanomas overexpressing vimentin and underexpressing E-cadherin tend to have a higher incidence of metastatic disease [9,13]. Therapy targeting vimentin overexpression and E-cadherin re-expression results in a significant reduction of tumor growth and invasiveness in vivo [14][15][16]. Thus, vimentin and Ecadherin represent useful biomarkers for classifying melanoma subtypes [17].…”

Section: Introductionmentioning

confidence: 95%

Antineoplastic effects of Rhodiola crenulata treatment on B16-F10 melanoma

et al. 2015

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Melanoma is an aggressive form of skin cancer with limited treatment options for advanced stage disease. Early detection and wide surgical excision remain the initial mode of treatment for primary tumors thus preventing metastases and leading to improved prognosis. Through this work, we have evaluated the antineoplastic effects of Rhodiola crenulata (R. crenulata) root extracts on the B16-F10 melanoma cell line, both in vitro and in vivo. We observed that R. crenulata treatment resulted in increased cell death as well as a reduction in tumor cell proliferation and migration in vitro. Additionally, we observed that R. crenulata decreased the expression of integrin β1 and vimentin and increased the expression of E-cadherin. Further, in mice treated with a topical R. crenulata-based cream therapy, tumors were more likely to have a radial growth pattern, a reduction in mitotic activity, and an increase in tumor necrosis. We also observed that mice drinking water supplemented with R. crenulata displayed a reduction of metastatic foci in disseminated models of melanoma. Collectively, these findings suggest that R. crenulata exhibits striking antitumorigenic and antimetastatic properties and that this extract may harbor potential novel adjuvant therapy for the treatment of melanoma.

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“…Prior work in our laboratories demonstrated that the removal or transformation of hydroxyl groups from natural products and replacement of these groups with functional groups capable of hydrogen bonding and van der Waals interactions led to new agents with singular and important biological targets. [8]…”

Section: Introductionmentioning

confidence: 99%

Antineoplastic Isoflavonoids Derived from Intermediate ortho‐Quinone Methides Generated from Mannich Bases

et al. 2016

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The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6 substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μM concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.

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Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis

Cited by 59 publications

References 26 publications

Anti-cancer activity of withaferin A in B-cell lymphoma

Anti-cancer activity of withaferin A in B-cell lymphoma

Antineoplastic effects of Rhodiola crenulata treatment on B16-F10 melanoma

Antineoplastic Isoflavonoids Derived from Intermediate ortho‐Quinone Methides Generated from Mannich Bases

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