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A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.

ABSTRACT: Hormone-refractory prostate cancer, its skeletal metastasis and complications remain a therapeutic challenge. Here we show that treatment with (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one (EM011), the brominated analogue of a plant-derived non-toxic antitussive alkaloid, noscapine, achieved significant inhibition of hormone-refractory human prostate cancer implanted intratibially in the bone as shown by non-invasive, real-time bioluminescent imaging of tumour growth in nude mice. Mechanistically, in vitro data suggested that the antiproliferative and proapoptotic effects of EM011 in human prostate cancer cell lines were through blockade of cell-cycle progression by impairing the formation of a bipolar spindle apparatus. The G2/M arrest was accompanied by activation of the mitotic checkpoint, a pre-requisite for induction of optimal apoptosis. Attenuation of mitotic checkpoint by siRNA duplexes led to a reduction in mitotic arrest and subsequent apoptosis. Our results further demonstrated participation of an intrinsic mitochondrially mediated apoptotic pathway that ultimately triggered caspase-driven EM011-induced apoptosis. EM011 did not exert any detectable toxicity in normal tissues with frequently dividing cells such as the gut and bone marrow. Thus, these data warrant further evaluation of EM011 for the management of prostate cancer.

SUBMITTER: Aneja R

PROVIDER: S-EPMC2883633 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.

Aneja Ritu R Miyagi Tohru T Karna Prasanthi P Ezell Tucker T Shukla Deep D Vij Gupta Meenakshi M Yates Clayton C Chinni Sreenivasa R SR Zhau Haiyen H Chung Leland W K LW Joshi Harish C HC

European journal of cancer (Oxford, England : 1990) 20100318 9

Hormone-refractory prostate cancer, its skeletal metastasis and complications remain a therapeutic challenge. Here we show that treatment with (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one (EM011), the brominated analogue of a plant-derived non-toxic antitussive alkaloid, noscapine, achieved significant inhibition of hormone-refractory human prostate cancer implanted intratibially in the bone as shown by non-in ...[more]

PMID: 20303260

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Project description:Thiadiazoles are one of the most widely utilized agents in medicinal chemistry, having a wide range of pharmacologic activity. Microtubules (MTs) have always remained a sought-after target in rapidly proliferating cancer cells. We screened for the growth inhibitory effect of synthetic 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles on cancer cells and identified NMK-TD-100, as the most potent agent. Cell viability experiments using human cervical carcinoma cell line (HeLa cells) indicated that the IC50 value was 1.42±0.11 µM for NMK-TD-100 for 48 h treatment. In further study, we examined the mode of interaction of NMK-TD-100 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. NMK-TD-100 induced arrest in mitotic phase of cell cycle, caused decline in mitochondrial membrane potential and induced apoptosis in HeLa cells. Immunofluorescence studies using an anti-α-tubulin antibody showed a significant depolymerization of the interphase microtubule network and spindle microtubule in HeLa cells in a concentration-dependent manner. However, the cytotoxicity of NMK-TD-100 towards human peripheral blood mononuclear cells (PBMC) was lower compared to that in cancer cells. Polymerization of tissue purified tubulin into microtubules was inhibited by NMK-TD-100 with an IC50 value of 17.5±0.35 µM. The binding of NMK-TD-100 with tubulin was studied using NMK-TD-100 fluorescence enhancement and intrinsic tryptophan fluorescence of tubulin. The stoichiometry of NMK-TD-100 binding to tubulin is 1:1 (molar ratio) with a dissociation constant of ~1 µM. Fluorescence spectroscopic and molecular modeling data showed that NMK-TD-100 binds to tubulin at a site which is very near to the colchicine binding site. The binding of NMK-TD-100 to tubulin was estimated to be ~10 times faster than that of colchicine. The results indicated that NMK-TD-100 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided insights into its potential of being a chemotherapeutic agent.

Dataset Information

A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.

Publications

A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.

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