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Jones R.J.,University of Texas M. D. Anderson Cancer Center | Baladandayuthapani V.,University of Texas M. D. Anderson Cancer Center | Neelapu S.,University of Texas M. D. Anderson Cancer Center | Fayad L.E.,University of Texas M. D. Anderson Cancer Center | And 5 more authors.
Blood | Year: 2011

Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G1/S and prompted us to examine combinations with the RNR inhibitor 2′,2′-difluoro- 2′-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNAmediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCLmurine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL. © 2011 by The American Society of Hematology.


Lin J.,Chinese PLA General Hospital | Wu Y.,Peking Union Medical College | Yang D.,Ascenta Therapeutics | Zhao Y.,Peking Union Medical College
Oncology Reports | Year: 2013

Gossypol is a naturally occurring polyphenolic compound extracted from cotton plants. Recent studies revealed that gossypol is a non-peptidic small molecule inhibitor of Bcl-2/Bcl-xl. The aim of the present study was to investigate the induction of apoptosis and antitumor effects of gossypol acetate in multiple myeloma and the possible mechanism(s) of action. Our results showed that gossypol acetate resulted in a dose- and time-dependent inhibition of multiple myeloma cell proliferation, with an IC50 value to both U266 and Wus1 cells at 2.4, 2.2 μM at 48 h after treatment. Gossypol acetate effectively induced the apoptosis of multiple myeloma cells as demonstrated by typical morphological changes, DNA ladder formation and increase in the percentage of cells in subdiploid peak. Furthermore, colorimetric assays showed activation of both caspase-3 and caspase-9. Bcl-2 and Bcl-xl expression was decreased by 86.5±1.2% and 35.9±3.6%, respectively, after treatment with gossypol acetate at 25 μmol/l for 24 h. Preliminary studies in vivo showed that a growth inhibition (T/C) of 30.9% (gossypol acetate 40 mg/kg) was obtained in Balb/C mice bearing Wus1 cells. In addition, there was no body weight loss for the treated group in comparison with the vehicle mice. Our results demonstrated that the potent inhibitor of Bcl-2 and Bcl-xl gossypol acetate had significant antiproliferative and antiapoptotic effects on multiple myeloma cells in vitro and in vivo. Gossypol acetate may represent a promising new anticancer agent with a novel molecular mechanism and warrants further investigation as a single agent, or in combination with other chemotherapeutics, for human multiple myeloma with Bcl-2 overexpression.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 106.00K | Year: 2005

DESCRIPTION (provided by applicant): Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves anti-apoptotic signal transduction pathways that prevent radiation-induced cell death. The inhibitors of apoptosis proteins (IAP) are important intrinsic cellular inhibitors of apoptosis, highly expressed in prostate and lung cancer cells, and play an important role in resistance to apoptosis induced by chemo/radiotherapy. Through computational structure-based 3D-database searching and rational design, a series of small molecule inhibitors of IAP have been discovered that showed promising therapeutic activity and specificity to overcome apoptosis-resistance in vitro in cancer cells with high levels of IAP. The specific aim of this Phase I STTR project is to investigate radiosensitization potential of the small molecule IAP inhibitors in vitro and especially in vivo in nude mouse xenograft models of human cancers of prostate and lung. The proposed studies will test the hypothesis that inhibition of anti-apoptotic activity of IAP by small molecule IAP inhibitors will overcome radioresistance and restore sensitivity of cancer cells to ionizing irradiation. The success of this Phase I STTR project will pave the way to Phase II STTR, aiming to develop the most potent small molecule inhibitor of IAP as a novel, molecular targeted approach for radiosensitizing human cancers with high levels of IAP, and as an entirely new class of anticancer therapy.


Patent
University of Michigan, Sanofi S.A. and Ascenta Therapeutics | Date: 2011-11-11

Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.


Sonpavde G.,Texas Oncology And Us Oncology Research | Matveev V.,Russian Academy of Medical Sciences | Burke J.M.,Rocky Mountain Cancer Centers | Caton J.R.,Willamette Valley Cancer Center | And 9 more authors.
Annals of Oncology | Year: 2012

Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.Patients and methods: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1 1. Patients received docetaxel (75 mg/m 2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS).Results: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months).Conclusions: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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