Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer

Sargeant, Aaron M.; Klein, Russell D.; Rengel, Robert C.; Clinton, Steven K.; Kulp, Samuel K.; Kashida, Yoko; Yamaguchi, Mamoru; Wang, Xingya; Chen, Ching‐Shih

doi:10.1080/01926230701338966

Cited by 32 publications

(33 citation statements)

References 46 publications

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“…Centrilobular hepatocellular hypertrophy was observed in mice from both groups receiving OSU-03012 treatments. Aside from this change, which we have reported previously (32), no significant lesions were detected in any tissues from animals subjected to histopathologic examination. To correlate these in vivo antitumor effects with mechanisms identified in vitro, intratumoral biomarkers of drug activity were assessed by immunohistochemistry and immunoblotting of tumor homogenates.…”

Section: Cancer Researchmentioning

confidence: 80%

Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors

et al. 2008

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Preexisting and acquired resistance to epidermal growth factor receptor (EGFR) inhibitors limits their clinical usefulness in patients with advanced non-small cell lung cancer (NSCLC). This study characterizes the efficacy and mechanisms of the combination of gefitinib or erlotinib with OSU-03012, a celecoxib-derived antitumor agent, to overcome EGFR inhibitor resistance in three NSCLC cell lines, H1155, H23, and A549. The OSU-03012/EGFR inhibitor combination induced pronounced apoptosis in H1155 and H23 cells, but not in A549 cells, suggesting a correlation between drug sensitivity and basal phospho-Akt levels independently of EGFR expression status. Evidence indicates that this combination facilitates apoptosis through both Akt signaling inhibition and upregulation of endoplasmic reticulum (ER) stress-induced, GADD153-mediated pathways. For example, ectopic expression of constitutively active Akt significantly attenuated the inhibitory effect on cell survival, and small interfering RNAmediated knockdown of GADD153 protected cells from undergoing apoptosis in response to drug cotreatments. Furthermore, the OSU-03012/EGFR inhibitor combination induced GADD153-mediated up-regulation of death receptor 5 expression and subsequent activation of the extrinsic apoptosis pathway. It is noteworthy that the ER stress response induced by this combination was atypical in that the cytoprotective pathway was not engaged. In addition, in vivo suppression of tumor growth and modulation of intratumoral biomarkers were observed in a H1155 tumor xenograft model in nude mice. These data suggest that the concomitant modulation of Akt and ER stress pathways with the OSU-03012/EGFR inhibitor combination represents a unique approach to overcoming EGFR inhibitor resistance in NSCLC and perhaps other types of cancer with elevated basal Akt activities. [Cancer Res 2008;68(8):2820-30]

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Section: Cancer Researchmentioning

confidence: 80%

Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors

et al. 2008

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“…Treatment was initiated 7 d after injection, with the gavage dose of drug adjusted twice weekly to mirror the dose of drug consumed in the diet. TRAMP mice (C57BL/6TRAMPxFVB) were generated and housed as previously reported (28). The reversibility of observed OSU-HDAC42-associated toxicity was determined in age-matched nontransgenic (wild-type) littermates of TRAMP mice, which included comparison of weights of the adrenal glands, brain, epididymides, epididymal fat pads, heart, kidneys, liver, pituitary gland, spleen, testes, and thymus.…”

Section: Methodsmentioning

confidence: 99%

“…An extended set of tissues from representative animals (n = 3, 5, and 10 for the pharmacodynamic, xenograft, and TRAMP studies, respectively) was evaluated microscopically in accordance with Society of Toxicologic Pathology-proposed guidelines for repeat-dosing toxicity studies (29), with the exception of spinal cord and female reproductive organs. Dorsal (DP), lateral (LP), ventral (VP), and anterior (AP) prostate lobes, iliac lymph nodes, liver (left lobe), and lungs from each TRAMP mouse were collected, fixed, processed, and evaluated as described (28). Testes were fixed for 24 h in Bouin's fixative and then transferred to 70% ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…TRAMP prostate tissue homogenates were prepared and immunoblotted against Ac-H3, p21, Ac-a-tubulin, a-tubulin, E-cadherin, synaptophysin, Bax, TAg, and h-actin as described (28). Immunohistochemical detection of Ac-H3, Ki67, cleaved caspase-3, E-cadherin, and synaptophysin was performed on 4-AM-thick, paraffinembedded PC-3 xenograft tumor, TRAMP prostate, testis, spleen, and/or bone marrow tissue sections in accordance with the manufacturers' recommendations.…”

Section: Methodsmentioning

confidence: 99%

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OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

Sargeant

Rengel²,

Kulp

et al. 2008

Cancer Research

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Histone deacetylase (HDAC) inhibitors suppress tumor cell growth via a broad spectrum of mechanisms, which should prove advantageous in the context of cancer prevention. Here, we examined the effect of dietary administration of OSU-HDAC42, a novel HDAC inhibitor, on prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Based on a series of pilot studies, an AIN-76A diet was formulated containing 208 ppm OSU-HDAC42, which was estimated to deliver f25 mg/kg of drug per day to each mouse and found to cause a suppression of PC-3 xenograft tumor growth equivalent to that achieved by gavage administration of a similar dose. At 6 weeks of age, TRAMP mice received this drug-containing or control diet for 4 or 18 weeks and were evaluated for prostatic intraepithelial neoplasia (PIN) and carcinoma development, respectively. OSU-HDAC42 not only decreased the severity of PIN and completely prevented its progression to poorly differentiated carcinoma (74% incidence in controls versus none in drug-treated mice), but also shifted tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively, at 24 weeks of age. This tumor suppression was associated with the modulation of intraprostatic biomarkers, including those indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. With the exception of completely reversible hematologic alterations and testicular degeneration, no significant changes in body weight or other indicators of general health were observed in drug-treated mice. These results suggest that OSU-HDAC42 has value in prostate cancer prevention. [Cancer Res 2008;68(10):3999-4009]

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“…Zhang et al (21) showed that the loss of mitochondrial membrane potential may be involved in OSU-03012-induced cell death in multiple myeloma cells. Furthermore, genomic inhibition of PDK1 was reported to suppress cardiac functions in the mouse heart (3,8,11), however, severe cardiac side effects of OSU-03012 were not reported at blood concentrations below 20 μM (6,15). To our knowledge, information on direct effects of OSU-03012 on cardiac function is absent.…”

mentioning

confidence: 66%

OSU-03012, a novel celecoxib derivative, induces cell swelling and shortens action potential duration in mouse ventricular cells

Yamamoto¹,

Iyoda²,

Kita³

et al. 2010

Biomed. Res.

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OSU03012, a novel celecoxib derivative, has been shown to inhibit proliferation and induce apoptosis in numerous cancer cell lines. However, not much is known about its influence on cell volume regulation and cardiac function in the mammalian heart. We examined the effects of OSU-03012 on cell volume and action potentials in mouse ventricular cells. Video image analysis showed that cell volume increased on application of OSU-03012 in a dose-dependent manner. The action potential duration (APD) at 50% and 90% repolarization (APD 50 and APD 90 respectively) as well as the resting membrane potential (RMP) were measured in current-clamp experiments. OSU-03012 had little effect on APD 50 and RMP but induced approximately 30% shortening of APD 90 . These results for cell volume and AP are similar to those in cells under ischaemia/hypoxia, and we confirmed that the shortening of APD 90 was almost completely recovered by glibenclamide, a potent inhibitor of ATP-sensitive potassium channels. We concluded that OSU-03012 may lead to cell swelling and shortening of AP via reduced ATP production in mouse ventricular cells.OSU-03012 has been shown to be a potent phosphoinositide-dependent kinase-1 (PDK1) inhibitor derived from the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib, but it does not possess COX-2 inhibitory activity (10,22). Celecoxib is used for preventing an increase in the number of cancer cells, which may be due to moderate apoptosis through blocking of PDK1/Akt signalling (22). OSU-03012 was shown to be a more potent inhibitor of cancer cell growth than celecoxib, and it inhibited both recombinant PDK1 activity and PC-3 cell viability with IC 50 values of about 5 μM (22). This new compound is currently undergoing preclinical development under the Rapid Access to Intervention Development Program at the National Cancer Institute. Until date, several mechanisms have been reported for OSO-03012-induced cell death. Zhang et al. (21) showed that the loss of mitochondrial membrane potential may be involved in OSU-03012-induced cell death in multiple myeloma cells. Furthermore, genomic inhibition of PDK1 was reported to suppress cardiac functions in the mouse heart (3, 8, 11), however, severe cardiac side effects of OSU-03012 were not reported at blood concentrations below 20 μM (6, 15). To our knowledge, information on direct effects of OSU-03012 on cardiac function is absent. In the present study, we examined the effect of OSU-03012 on cardiac cell volume and action potential (AP) in an attempt to elucidate the effect of this compound on cardiac function. Fukuoka University Animal Care and Use Committee approved the use and treatment of all animals included in the experiments described here. Single ventricular cells from mice (18-25 g, C-57BL/6J/ black inbred, male) anaesthetised with sodium pentobarbitone (50 mg/mL, I.P.) were isolated by an enzymatic dispersion technique (20). The stock and A two-tailed probability of < 0.05 indicated statistical significance. Figure 1A and B represent typical vi...

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Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer

Cited by 32 publications

References 46 publications

Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors

Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors

OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

OSU-03012, a novel celecoxib derivative, induces cell swelling and shortens action potential duration in mouse ventricular cells

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