UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

Mizuno, Keiko; Noda, K; Ueda, Yoshihiko; Hanaki, Hisao; Saido, Takaomi C.; Ikuta, Tohgo; Kuroki, Toshio; Tamaoki, Tatsuya; Hirai, Syu-ichi; Osada, Shin‐Ichi; Ohno, Shigeo

doi:10.1016/0014-5793(95)00042-8

Cited by 72 publications

(44 citation statements)

References 21 publications

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“…Indeed, UCN-01 was originally developed as a PKC inhibitor (52) and was later shown to target cell cycle regulators (53). However, although inhibition of PI3K with wortmannin and LY 294002, and thus of Akt, prevented vGPCR-stimulated endothelial cell proliferation, the treatment of EC-vGPCR with a PKC-specific inhibitor (GFX) at effective concentrations (1-10 M) failed to reproduce the profound inhibitory effect on cell proliferation demonstrated by therapeutic concentrations of UCN-01 (results not shown).…”

Section: Discussionmentioning

confidence: 99%

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Sodhi

Montaner

Patel

et al. 2004

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

140

132

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We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus͞human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis. Examination of KS biopsies from AIDS patients revealed active Akt as a prominent feature, supportive of a role for Akt in human Kaposi's sarcomagenesis. By using a vGPCR agonist-dependent mutant, we further establish constitutive activity as a requirement for vGPCR sarcomagenesis, validating targeted inhibition of key vGPCR signaling pathways as an approach for preventing its oncogenic potential. These observations prompted us to explore the efficacy of inhibiting Akt activation as a molecular approach to KS treatment. Pharmacological inhibition of the Akt pathway with the chemotherapeutic agent 7-hydroxystaurosporine prevented proliferation of vGPCR-expressing endothelial cells in vitro and inhibited their tumorigenic potential in vivo. Both were associated with a decrease in Akt activity. These results identify Akt as an essential player in vGPCR sarcomagenesis and demonstrate the therapeutic potential of drugs targeting this pathway in the treatment of KS.human herpesvirus 8 ͉ Kaposi's sarcoma-associated herpesvirus ͉ 7-hydroxystaurosporine

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Section: Discussionmentioning

confidence: 99%

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Sodhi

Montaner

Patel

et al. 2004

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

140

132

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“…Staurosporine binds with the kinase domain of PKC that interferes in the binding of ATP, resulting in the inhibition of kinase activity [16,17]. NIH3T3 cells were transfected with the pGFP3PKCα-WT, pGFP3-PKCβ1-WT, pGFP3-PKCβ2-WT, pGFP3-PKCγ-WT, pGFP3-PKCδ-WT, pGFP3-PKCε-WT plasmids.…”

Section: Effect Of Staurosporine On Tpa Induced Translocationmentioning

confidence: 99%

Isoform-specific translocation of PKC isoforms in NIH3T3 cells by TPA

Kazi

Soh

2007

Biochemical and Biophysical Research Communications

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Protein kinase C (PKC), a multi-gene family of enzymes, plays key roles in the pathways of signal transduction, growth control and tumorigenesis. Variations in the intracellular localization of the individual isoforms are thought to be an important mechanism for the isoform-specific regulation of enzyme activity and substrate specificity. To provide a dynamic method of analyzing the localization of the specific isoforms of PKC in living cells, we generated fluorescent fusion proteins of the various PKC isoforms by using the green fluorescent protein (GFP) as a fluorescent marker at the carboxyl termini of these enzymes. The intracellular localization of the specific PKC isoforms was then examined by fluorescence microscopy after transient transfection of the respective PKC-GFP expression vector into NIH3T3 cells and subsequent TPA stimulation. We found that the specific isoforms of PKC display distinct localization patterns in untreated NIH3T3 cells. For example, PKCα is localized mainly in the cytoplasm while PKCε is localized mainly in the Golgi apparatus. We also observed that PKCα, β1, β2, γ, δ, ε, and η translocate to the plasma membrane within 10 min of the start of TPA treatment, while the cellular localizations of PKCζ and ι were not affected by TPA. Using a protein kinase inhibitor, we also showed that the kinase activity was not important for the translocation of PKC. These results suggest that specific PKC isoforms exert spatially distinct biological effects by virtue of their directed translocation to different intracellular sites.

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“…UCN-01 exerts antiproliferative activity both in vitro and in vivo, an action that may be related to inhibition of protein kinase C isoforms (2). UCN-01 also enhances the cytotoxicity of chemotherapeutic agents by several postulated mechanisms, including inhibition of Chk1 (3).…”

Section: Introductionmentioning

confidence: 99%

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

Hamed

Hawkins

Mitchell

et al. 2008

Molecular Cancer Therapeutics

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The present studies were initiated to determine in greater molecular detail how MEK1/2 inhibitors [PD184352 and AZD6244 (ARRY-142886)] interact with UCN-01 (7-hydroxystaurosporine) to kill mammary carcinoma cells in vitro and radiosensitize mammary tumors in vitro and in vivo and whether farnesyl transferase inhibitors interact with UCN-01 to kill mammary carcinoma cells in vitro and in vivo. Expression of constitutively activated MEK1 EE or molecular suppression of JNK and p38 pathway signaling blocked MEK1/2 inhibitor and UCN-01 lethality, effects dependent on the expression of BAX, BAK, and, to a lesser extent, BIM and BID. In vitro colony formation studies showed that UCN-01 interacted synergistically with the MEK1/2 inhibitors PD184352 or AZD6244 and the farnesyl transferase inhibitors FTI277 and R115,777 to kill human mammary carcinoma cells. Athymic mice carrying f100 mm 3 MDA-MB-231 cell tumors were subjected to a 2-day exposure of either vehicle, R115,777 (100 mg/kg), the MEK1/2 inhibitor PD184352 (25 mg/kg), UCN-01 (0.2 mg/kg), or either of the drugs in combination with UCN-01. Transient exposure of tumors to R115,777, PD184352, or UCN-01 did not significantly alter tumor growth rate or the mean tumor volume in vivo f15 to 30 days after drug administration. In contrast, combined treatment with R115,777 and UCN-01 or with PD184352 and UCN-01 significantly reduced tumor growth. Tumor cells isolated after combined drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than tumor cells that were exposed to either drug individually. Irradiation of mammary tumors after drug treatment, but not before or during treatment, significantly enhanced the lethal effects of UCN-01 and MEK1/2 inhibitor treatment. These findings argue that UCN-01 and multiple inhibitors of the RAS-MEK pathway have the potential to suppress mammary tumor growth, and to interact with radiation, in vitro and in vivo.

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UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

Cited by 72 publications

References 21 publications

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Isoform-specific translocation of PKC isoforms in NIH3T3 cells by TPA

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

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