BPR0L075, a Novel Synthetic Indole Compound with Antimitotic Activity in Human Cancer Cells, Exerts Effective Antitumoral Activity<b><i>in Vivo</i></b>

Kuo, Ching Chuan; Hsieh, Hsing Pang; Pan, Wen; Chen, Ching Ping; Liou, Jing Ping; Lee, Shiow Ju; Chang, Yi Ling; Chen, Li Tzong; Chen, Chiung Tong; Chang, Jang Yang

doi:10.1158/0008-5472.can-03-3474

Cited by 193 publications

(195 citation statements)

References 34 publications

(32 reference statements)

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“…The subsequent G 2 -M transition is mainly regulated by cyclin B-Cdk1 activity, which is suppressed by Cdk1 phosphorylation on tyrosine 15 during G 2 /M (11). Recent studies showed that tumor cell cycle arrest at G 2 /M is associated with an increase in cyclin B1 (12). In addition to inhibiting Cdk-2, -4, and -6 activities and promoting G 1 -synthetic phase transition, p21 CIP1 can accumulate in nuclei near the G 2 /M boundary and cause a transient block in late G 2 phase (10).…”

Section: Discussionmentioning

confidence: 99%

Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

Chang

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

178

157

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Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G0/G1 arrest; in contrast, shear stress (12 dynes/cm 2 ) induced G2/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21 CIP1 and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27 KIP1 as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G2/M arrest and corresponding changes in G2/M regulatory protein expression and activity were mediated by ␣v␤3 and ␤1 integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by ␣v␤3 and ␤1 integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G2/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells.M echanical microenvironment plays important roles in modulating tissue development, maintenance, and remodeling and in cellular responses and functions (1). Interstitial fluid flow in and around tissue affects the mechanical microenvironment, including the shear stress and pressure force acting on the cell surface and the tethering force acting on cell-matrix connections (2). These interstitial flow-induced forces can modulate tumor metastasis and invasion as well as anticancer drug delivery (3).Although the influence of interstitial fluid flow on tumor pathobiology and drug delivery has been studied, the effect of the flow-induced shear force on tumor cells has not been much explored. Compressive forces have been shown to inhibit tumor cell growth (4) and up-regulate adhesion molecules (5). A recent study reported that tumor cell proliferation is affected by intratumoral pressure and that activation of mitogen-activated protein kinases and nuclear antigen Ki-67 is involved in this mechanical modulation (6). Although these results show that mechanical forces can modulate tumor cell responses, the detailed mechanisms by which mechanical stimuli are transduced into cellular signaling to regulate tumor cell gene expression and functions remain unclear.Integrins have been implicated as mechanosensors in many types of cells seeded on extracellular matrix (ECM) (7), but their role in modulating mechanical responses of...

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Section: Discussionmentioning

confidence: 99%

Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

Chang

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

178

157

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“…The measurement was done according to the method described by Kuo et al 6 The change of the MMP after SK228 treatment was measured by FACS Calibur Flow cytometer (BD). Cells were pre-treated with 4 lM Cyclosporine A (Millipore), an inhibitor of mitochondrial permeability transition pore (mPTP), for 30 min prior to SK228 treatment in MMP assay.…”

Section: Mitochondrial Membrane Potential Measurementmentioning

confidence: 99%

“…I3C and its metabolites inhibited proliferation, cell cycle progression and cell survival and induced cell death in several cancer cell lines. 5 Synthetically developed indole compounds, for example, BPR0L075, caused G2/M arrest and apoptosis, 6 JKA97 has been shown to induce a p53-independent and Bax-dependent apoptosis in human colon cancer cells in vitro and in vivo. 7 We previously developed a novel 2-step synthesized indole compound, 1,1,3-tri(3-indolyl)cyclohexane (3-indole), which exhibits anticancer growth effect in human lung cancer cell lines (A549, H1299 and CL1-1).…”

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confidence: 99%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

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“…The colchicine, paclitaxel, and vinblastine competitionbinding scintillation proximity assay (SPA) were conducted as described previously (20) using biotin-labeled tubulin and streptavidin-labeled polyvinyl toluene SPA beads to determine whether the test compound exerts direct Tubulin-binding capacity. The in vitro tubulin polymerization assay and in vivo microtubule assembly assay were conducted as described previously (20) to evaluate the effect of test compound on microtubule assembly.…”

Section: Tubulin Targeting Analysismentioning

confidence: 99%

“…The in vitro tubulin polymerization assay and in vivo microtubule assembly assay were conducted as described previously (20) to evaluate the effect of test compound on microtubule assembly. Detail experimental protocols are described in Supplementary Document.…”

Section: Tubulin Targeting Analysismentioning

confidence: 99%

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

Cheng

Liou

Kuo

et al. 2013

Molecular Cancer Therapeutics

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Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1a (HIF-1a) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1a mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC 50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC 50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G 2 -M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGFinduced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1a protein but also destabilized HIF-1a mRNA. The mechanism of causing unstable of HIF-1a mRNA by MPT0B098 is through decreasing RNAbinding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1a of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies. Mol Cancer Ther; 12(7); 1202-12. Ó2013 AACR.

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BPR0L075, a Novel Synthetic Indole Compound with Antimitotic Activity in Human Cancer Cells, Exerts Effective Antitumoral Activityin Vivo

Cited by 193 publications

References 34 publications

Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

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