The Development of Pro-Apoptotic Cancer Therapeutics

Ziedan, Nesreen I.; Kadri, Hachemi; Westwell, Andrew D.

doi:10.2174/138955708784567430

Cited by 15 publications

(12 citation statements)

References 58 publications

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“…The induction of apoptosis in cancer cells has emerged as an exciting possibility for the development of selective cancer therapies [37]. Apoptosis is characterized by distinct morphological features such as cell shrinkage, loss of contact with neighboring cells, formation of cytoplastic vacuoles, chromatin condensation, nuclear-membrane blebbing, oligonucleosomal DNA fragmentation, and finally breakdown of the cell into smaller units (apoptotic bodies).…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic and Apoptosis-Inducing Activity of Triterpene Glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 Cells

et al. 2014

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The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in HepG2 cells was further investigated by determining its effect on the morphology, mitochondrial transmembrane potential (Δψm) and mRNA expression levels of the apoptosis-related genes. The results showed that the number of glycosyl residues in sugar chains and the side chain of aglycone could affect their cytotoxicity towards tumor cells and selective cytotoxicity. 1 significantly inhibited cell viability and induced apoptosis in HepG2 cells. 1 also markedly decreased the Δψm and Bcl-2/Bax mRNA express ratio, and up-regulated the mRNA expression levels of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. Therefore, 1 induced apoptosis in HepG2 cells through both intrinsic and extrinsic pathway. These findings could potentially promote the usage of these glycosides as leading compounds for developing new antitumor drugs.

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Section: Resultsmentioning

confidence: 99%

Cytotoxic and Apoptosis-Inducing Activity of Triterpene Glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 Cells

et al. 2014

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“…Resistance to apoptosis is one of the fundamental hallmarks of cancer. Recently, the selective induction of apoptosis in cancer cells has emerged as an exciting possibility for the development of future selective cancer therapies [26].…”

Section: Discussionmentioning

confidence: 99%

Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress–induced apoptosis

Zha

Fan

Sun

et al. 2012

Journal of Pineal Research

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Endoplasmic reticulum stress-mediated cell apoptosis is implicated in the development of cancer. Melatonin induces apoptosis in hepatocellular carcinoma (HCC) in experimental studies, but the effects of melatonin on endoplasmic reticulum (ER) stress-induced apoptosis in HCC have not been tested. Differences in ER stress-induced apoptosis in human hepatoma cells and normal human hepatocyte were investigated by exposure to tunicamycin (ER stress inducer). Significant differences were observed in the rate of apoptosis between HepG2 cells (hepatoma cells) and HL-7702 cells (normal human hepatocyte cells). The expression of cyclooxygenase-2 (COX-2) was increased in HepG2 cells but not in HL-7702 cells. Furthermore, down-regulation of COX-2 expression using the COX-2 inhibitor, celecoxib, increased tunicamycin-induced apoptosis concomitant with the up-regulation of pro-apoptotic transcription factor CHOP (GADD153) and down-regulation of B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, suggesting that inhibition of COX-2 sensitized human hepatoma cells to ER stress-induced apoptosis. Interestingly, co-treatment with tunicamycin and melatonin also decreased the expression of COX-2 and significantly increased the rate of apoptosis by elevating the levels of CHOP and reducing the Bcl-2/Bax ratio. These results demonstrate that melatonin sensitizes human hepatoma cells to ER stress-induced apoptosis by down-regulating COX-2 expression, increasing the levels of CHOP and decreasing the Bcl-2/Bax ratio.

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“…The so-called 'Amyloid Cascade' involving caspase enzymes may actually be a downstream consequence of mitochondrial toxicity (Townsend et al, 2007;Selkoe and Wolfe, 2007;Walsh and Selkoe, 2007;Dunys et al, 2007;Lee et al, 2007). APOE4 and APOE3 fragments without the C-terminal region may well be a form of pro-apoptotic death signals, often discussed in the oncology literature, with APP one of many catabolized moleculesFbut one which forms aggregates in tissue (Ziedan et al, 2008;Ashkenazi and Herbst, 2008;Hisatomi et al, 2008;Mahley et al, 2006;Roses et al, 2007a).…”

Section: Genome-wide Association Interpretationsfthe 'Linkage' Of Thementioning

confidence: 99%

The Medical and Economic Roles of Pipeline Pharmacogenetics: Alzheimer's Disease as a Model of Efficacy and HLA-B*5701 as a Model of Safety

Roses

2008

Neuropsychopharmacol

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Pharmacogenetics (PGX) is the study of drug response as a function of an individual's DNA. PGX is often viewed as an extension of disease association genetics, and although this information may be related, it is not the study of drug response. Although medicines are used to treat diseases, the value of strategies that identify and incorporate DNA biomarkers associated with clinical efficacy, or DNA biomarkers for untoward clinical responses, can be applied directly to pharmaceutical pipelines. The growth of adverse event PGX studies involving marketed medicines generally uses relatively large numbers of affected patients, but has been productive. However, the two critical strategies for pipeline genetics must make use of fewer patients: (1) the early identification of efficacy signals so that they can be applied early in development for targeted therapies and (2) identification of safety signals that can subsequently be validated prospectively during development using the least number of patients with adverse responses. Assumptions are often made that large numbers of patients are necessary to recognize PGX hypotheses and to validate DNA biomarkers. In some ways, pipeline pharmacogenetics may be viewed as the opposite of current genome-wide scanning designs. The goal is to obtain PGX signals in as few patients as possible, and then validate PGX hypotheses for specificity and sensitivity as development trials go forward--not using hundreds of thousand of markers to detect strong linkage disequilibrium signals in thousands of patients and their controls. Drug development takes 5-7 years for a drug candidate to traverse to registration--and this is similar to the timeframe for validating genetic biomarkers using sequential clinical trials. Two important examples are discussed, the association of APOE genotypes to the demonstration of actionable efficacy signals for the use of rosiglitazone for Alzheimer's disease; and the identification of HLA-B(*)5701 as a highly sensitive and specific predictive marker for abacavir treated patients who will develop hypersensitivity syndrome (HSS). The rosiglitazone study prevented pipeline attrition by changing the interpretation of a critical Phase IIB proof of concept study (2005) from a failed study, to a positive efficacy response in a genetically predictable proportion of patients. Now, three years later, a Phase III program of clinical trials using pharmacogenetic designs is months away from completion (late08). If successfully registered (early09), millions of patients could benefit, and efficacy PGX would have achieved its first prospective block-buster. The use of safety candidate gene association genetics in patients who received abacavir therapy and developed HSS starting in 1998 culminated in a double blind clinical trial that determined sensitivity > 97% and specificity >99% in 2007. Clinical consensus panels rapidly recommended abacavir as the preferred therapy along with HLA-B(*)5701 pre-testing, immediately increasing the market share of abacavir with respect to ot...

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The Development of Pro-Apoptotic Cancer Therapeutics

Cited by 15 publications

References 58 publications

Cytotoxic and Apoptosis-Inducing Activity of Triterpene Glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 Cells

Cytotoxic and Apoptosis-Inducing Activity of Triterpene Glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 Cells

Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress–induced apoptosis

The Medical and Economic Roles of Pipeline Pharmacogenetics: Alzheimer's Disease as a Model of Efficacy and HLA-B*5701 as a Model of Safety

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