Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

Shimoyama, Tae; Hamano, Takaichi; Natsume, Tsugitaka; Koizumi, Fumiaki; Kiura, Katsuyuki; Tanimoto, Mitsune; Nishio, Kazuto

doi:10.1038/sj.tpj.6500386

Cited by 6 publications

(6 citation statements)

References 35 publications

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“…The similarities and differences in mechanisms between classes of compounds sharing the same molecular target have been characterized using genomic profiling (7). In the present study, we used pharmacologic and genomic profiling in the CEPH cell lines to investigate two classes of Top1 inhibitors, the camptothecins and the indenoisoquinolines.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of histone H2AX is an extremely sensitive marker for double strand breaks induced by DNA damaging agents, such as the camptothecins and indenoisoquinolines (5, 6). It has been suggested that other histones are involved in DNA repair and cell proliferation (7). Studies indicate that histones are ADP-ribosylated in vivo in response to DNA damage (8).…”

Section: Discussionmentioning

confidence: 99%

“…Compound-to-compound comparative studies between structurally distinct compounds sharing a molecular target have been used to identify genes and pathways which are involved in a shared general mechanism and those which are class-specific (7, 8). Our own familial genetics strategy is one of the latest genomic tools for dissecting mechanisms of compound action and comparing genomic profiles across compound classes (Peters, EJ; Motsinger-Reif, A; Havener, TM; Everitt, L; Hardison, NE; Watson, VG; Richards, K; Province, MA; McLeod, HL.…”

Section: Introductionmentioning

confidence: 99%

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Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines

Watson

Hardison²,

Harris³

et al. 2011

Molecular Cancer Therapeutics

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We have attempted to use a familial genetics strategy to study mechanisms of Topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds, interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of fifteen families of CEPH cell lines (n = 142) to nine camptothecin analogues. Linkage analysis revealed a pattern of seven quantitative trait loci (QTLs) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin-specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top 1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining three QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, eight QTLs were identified which were unique to the indenoisoquinolines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines

Watson

Hardison²,

Harris³

et al. 2011

Molecular Cancer Therapeutics

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“…While clinical trials of dolastatin 10 have been terminated, several other dolastatin analogs are currently in clinical development (Flahive and Srirangam 2005) The synthetic derivative TZT-1027 (auristatin PE or soblidotin) is in Phase II clinical trials and has been shown to exhibit potent anti-vascular effects in addition to anti-tubulin activity, suggesting that a dual mechanism might well be possible with this agent (Shimoyama et al 2006). The analog cematodin (LU-103793) has progressed into Phase II clinical trials against malignant melanoma, metastatic breast cancer and non-small-cell lung cancer, and while no objective responses have been reported, there are reports of stable disease being seen in both the melanoma and breast cancer trials and a subjective increase in a quality of life measure in the lung trial (Flahive and Srirangam 2005).…”

Section: Some Marine-derived Anticancer Agentsmentioning

confidence: 99%

Nature: a vital source of leads for anticancer drug development

2009

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Over 60% of the current anticancer drugs have their origin in one way or another from natural sources. Nature continues to be the most prolific source of biologically active and diverse chemotypes, and it is becoming increasingly evident that associated microbes may often be the source of biologically active compounds originally isolated from host macro-organisms. While relatively few of the actual isolated compounds advance to become clinically effective drugs in their own right, these unique molecules may serve as models for the preparation of more efficacious analogs using chemical methodology such as total or combinatorial (parallel) synthesis, or manipulation of biosynthetic pathways. In addition, conjugation of toxic natural molecules to monoclonal antibodies or polymeric carriers specifically targeted to epitopes on tumors of interest can lead to the development of efficacious targeted therapies. The essential role played by natural products in the discovery and development of effective anticancer agents, and the importance of multidisciplinary collaboration in the generation and optimization of novel molecular leads from natural product sources is reviewed.

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“…Sources of elevated ROS production include mitochondria and plasma membrane oxidase [17]. It has been reported that exposure to toxic core metals can induce high levels of ROS generation, which in turn can increase lipid peroxidation, reduce cell membrane integrity and result in oxidative damage to DNA and cellular proteins, leading to cell death [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures

Wang

Song

et al. 2015

Biol Trace Elem Res

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Cadmium (Cd) induces significant oxidative damage in cells. Recently, it was reported that autophagy could be induced by Cd in neurons. However, little is known about the role of reactive oxygen species (ROS) during Cd-induced autophagy. In our study, we examined the cross-talk between ROS and autophagy by using N-acetyl cysteine (NAC, an antioxidant) and chloroquine (CQ, a pharmacological inhibitor of autophagy) in a primary rat neuronal cell cultures. We observed accumulation of acidic vesicular organelles and the increased expression of endogenous protein light chain 3 (LC3) in Cd-treated neurons, revealing that Cd induced a high level of autophagy. Moreover, increased levels of ROS were observed in neurons treated with Cd, showing that ROS accumulation was closely associated with neuron's exposure to Cd. Furthermore, we found that autophagy was inhibited by using CQ and/or NAC with further aggravation of mitochondrial damage, lactate dehydrogenase (LDH) leakage and hypoploid apoptotic cell number in Cd-treated neurons. These results proved that autophagy has a cytoprotective role during Cd-induced toxicity in neurons, and it can prevent the oxidative damage. These findings may enable the development of novel therapeutic strategies for neurological diseases.

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Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

Cited by 6 publications

References 35 publications

Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines

Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines

Nature: a vital source of leads for anticancer drug development

Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures

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