scholarly journals Small-molecule SMAC mimetics as new cancer therapeutics

2014 ◽  
Vol 144 (1) ◽  
pp. 82-95 ◽  
Author(s):  
Longchuan Bai ◽  
David C. Smith ◽  
Shaomeng Wang
Keyword(s):  
Small Molecule ◽  
Cancer Therapeutics ◽  
Smac Mimetics

A ratiometric colorimetric detection of the folate receptor based on terminal protection of small-molecule-linked DNA

The Analyst ◽  
2015 ◽  
Vol 140 (4) ◽  
pp. 1260-1264 ◽  
Author(s):  
Yanhong Zhu ◽  
Guangfeng Wang ◽  
Liang Sha ◽  
Yuwei Qiu ◽  
Hong Jiang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Crucial Role ◽  
Folate Receptor ◽  
Low Cost ◽  
Colorimetric Detection ◽  
Cancer Therapeutics ◽  
Selective Detection

Development of strategies for the sensitive and selective detection of the folate receptor (FR) that are simple and low cost is of great importance for assessing cancer therapeutics due to its crucial role in physiological, pharmacological and pathological processes.

scholarly journals Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations

2019 ◽  
Vol 383 ◽  
pp. 114771
Author(s):  
Ognian C. Ikonomov ◽  
Diego Sbrissa ◽  
Assia Shisheva
Keyword(s):  
Small Molecule ◽  
Cancer Therapeutics

scholarly journals Protein kinase Cδ inactivation inhibits cellular proliferation and decreases survival in human neuroendocrine tumors

2011 ◽  
Vol 18 (6) ◽  
pp. 759-771 ◽  
Author(s):  
Zhihong Chen ◽  
Lora W Forman ◽  
Kenneth A Miller ◽  
Brandon English ◽  
Asami Takashima ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Small Molecule ◽  
Cellular Proliferation ◽  
Small Molecule Inhibitors ◽  
Cancer Therapeutics ◽  
Therapeutic Modality ◽  
Ras Signaling ◽  
Normal Tissues ◽  
Induced Apoptosis

The concept of targeting cancer therapeutics toward specific mutations or abnormalities in tumor cells, which are not found in normal tissues, has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. Many human malignancies display activating mutations in the Ras family of signal-transducing genes or over-activity of p21Ras-signaling pathways. Carcinoid and other neuroendocrine tumors have been similarly demonstrated to have activation of Ras signaling directly by mutations in Ras, indirectly by loss of Ras-regulatory proteins, or via constitutive activation of upstream or downstream effector pathways of Ras, such as growth factor receptors or PI3-kinase and Raf/mitogen-activated protein kinases. We previously reported that aberrant activation of Ras signaling sensitizes cells to apoptosis when the activity of the PKCδ isozyme is suppressed and that PKCδ suppression is not toxic to cells with normal levels of p21Rassignaling. We demonstrate here that inhibition of PKCδ by a number of independent means, including genetic mechanisms (shRNA) or small-molecule inhibitors, is able to efficiently and selectively repress the growth of human neuroendocrine cell lines derived from bronchopulmonary, foregut, or hindgut tumors. PKCδ inhibition in these tumors also efficiently induced apoptosis. Exposure to small-molecule inhibitors of PKCδ over a period of 24 h is sufficient to significantly suppress cell growth and clonogenic capacity of these tumor cell lines. Neuroendocrine tumors are typically refractory to conventional therapeutic approaches. This Ras-targeted therapeutic approach, mediated through PKCδ suppression, which selectively takes advantage of the very oncogenic mutations that contribute to the malignancy of the tumor, may hold potential as a novel therapeutic modality.

scholarly journals Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

2015 ◽  
Vol 112 (18) ◽  
pp. 5803-5808 ◽  
Author(s):  
Gregor Ebert ◽  
Cody Allison ◽  
Simon Preston ◽  
James Cooney ◽  
Jesse G. Toe ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Cancer Therapeutics ◽  
Hbv Infection ◽  
Core Antigen ◽  
Therapeutic Implications ◽  
Endogenous Protein ◽  
Tumor Killing ◽  
Smac Mimetics ◽  
Infected Cells ◽  
Cellular Inhibitors

We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4+ T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.

scholarly journals Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol

2015 ◽  
Vol 113 (8) ◽  
pp. 1158-1167 ◽  
Author(s):  
Yu-chi Shen ◽  
Ravi Upadhyayula ◽  
Stephanie Cevallos ◽  
Ryan J Messick ◽  
Tammy Hsia ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cancer Therapeutics ◽  
Multiple Modes ◽  
Modes Of Action

Differential involvement of TAK1, RIPK1 and NF-κB signaling in Smac mimetic-induced cell death in breast cancer cells

2019 ◽  
Vol 400 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Nadine Schmidt ◽  
Lisa Kowald ◽  
Sjoerd J.L. van Wijk ◽  
Simone Fulda
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cell Death ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Cancer Therapeutics ◽  
Breast Cancer Cell Lines ◽  
Smac Mimetics

Abstract Smac mimetics (SMs) are considered promising cancer therapeutics. However, the mechanisms responsible for mediating cell death by SMs are still only partly understood. Therefore, in this study, we investigated signaling pathways upon treatment with the bivalent SM BV6 using two SM-sensitive breast cancer cell lines as models. Interestingly, genetic silencing of transforming growth factor (TGF)β activated kinase (TAK)1, an upstream activator of the nuclear factor-kappaB (NF-κB) subunit RelA (p65), increased BV6-induced cell death only in EVSA-T cells, although it reduced BV6-mediated upregulation of tumor necrosis factor (TNF)α in both EVSA-T and MDA-MB-231 cells. By comparison, genetic silencing of p65, a key component of canonical NF-κB signaling, blocked BV6-induced cell death in MDA-MB-231 but not in EVSA-T cells. Similarly, knockdown of NF-κB-inducing kinase (NIK) rescued MDA-MB-231 cells from BV6-induced cell death, while it failed to do so in EVSA-T cells. Consistently, silencing of p65 or NIK reduced BV6-stimulated upregulation of TNFα in MDA-MB-231 cells. In conclusion, TAK1, receptor-interacting kinase 1 (RIPK1) as well as canonical and non-canonical NF-κB signaling are differentially involved in SM-induced cell death in breast cancer cells. These findings contribute to a better understanding of SM-induced signaling pathways.

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