A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death

Bucur, Octavian; Gaidos, Gabriel; Yatawara, Achani K.; Pennarun, Bodvaël; Rupasinghe, Chamila N.; Roux, Jérémie; Andrei, Ștefan; Guo, Bingqian; Panaitiu, Alexandra E.; Pellegrini, Maria; Mierke, Dale F.; Khosravi‐Far, Roya

doi:10.1038/srep09893

Cited by 23 publications

(15 citation statements)

References 38 publications

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“…For example, Bucur et al (2015) synthesized a small molecule that binds caspase 8 and enhances its activation when combined with TRAIL inducing apoptosis in Jurkat cells. Furthermore, Lin et al (2010) demonstrated that SMI-4a, a small molecule inhibitor of Pim kinases, kill a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma being highly sensitive.…”

Section: Discussionmentioning

confidence: 99%

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

et al. 2016

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Molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer. Many targeted therapies were approved by Food and Drug Administration as standard treatment, others were introduced into preclinical or clinical studies on hematological malignancies (HMs). The development of drug-resistance in some HMs and the lack of effective treatments in other ones emphasized the need for searching new molecular targets and therapeutic agents. The aim of this study was to evaluate the effects of 4c pyrazolo[3,4-d]pyrimidine compound, a Src inhibitor, on lymphoid and myeloid neoplasms. Here, we demonstrated its ability to reduce cell viability, induce apoptosis and cell cycle arrest in lymphoid cell lines such as Jurkat, SKMM1, Derl-2/7, and myeloid cell lines, such as Jurl-MK1. Moreover, we reported a high expression of a Src kinase, Fyn, in these cell lines compared to healthy subjects. This study was a starting point to investigate 4c pyrazolo[3,4-d]pyrimidine compound as a drug for HMs and Src kinases as its potential molecular targets.

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Section: Discussionmentioning

confidence: 99%

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

et al. 2016

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“…An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase-8 activation. Through an in silico screening some authors successfully found a small molecule activator of caspase-8 [ 79 ]. Experimental validation performed in multiple cell lines, such as leukemic and prostate cells, revealed that CaspPro small molecule promotes caspase-8 activation, caspase-3 activation and PARP cleavage, in the presence of TRAIL, leading to cell death [ 79 ].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Pistritto

Trisciuoglio²,

Ceci

et al. 2016

Aging

1,255

792

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Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

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“…Alternatively, caspase 8 activation caused by the down-regulation of c-FLIP at the transcriptional or posttranslational levels underlies the mode of action of some TRAIL sensitizers [ 45 ]. Likewise, small molecules that bind and stabilize the caspase 8 homodimers can function as TRAIL stabilizers by promoting caspase 8 activation upon TRAIL stimulation [ 56 ]. Chemotherapeutic drugs synergize with TRAIL mainly through lowering the apoptotic threshold by up-regulating proapoptotic BH3-only proteins while down-regulating antiapoptotic BCL-2 proteins and/or IAPs [ 39 ].…”

Section: Trailmentioning

confidence: 99%

A promising “TRAIL” of tanshinones for cancer therapy

Chang

2015

BioMed

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An ideal cancer therapy specifically targets cancer cells while sparing normal tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) elicits apoptosis by engaging its cognate death receptors (DRs—namely, DR4 and DR5. The cancer cell-selective proapoptotic action of TRAIL is highly attractive for cancer therapy, but clinical application of TRAIL is rather limited due to tumors’ inherent or acquired TRAIL resistance. Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis. Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers. In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese). Research from our laboratories and others have revealed the synergy of a tanshinones-TRAIL combination in diverse types of cancer cells through up-regulation of DR5 and/or down-regulation of antiapoptotic proteins such as survivin. Thus, in addition to their anticancer mechanisms, tanshinones as TRAIL sensitizers hold great potential to be translated to TRAIL-based therapeutic modalities for combatting cancer.

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A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death

Cited by 23 publications

References 38 publications

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

A promising “TRAIL” of tanshinones for cancer therapy

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