Retinoids, RAMBAs, and Histone Deacetylase Inhibitors

类维生素A、RAMBA 和组蛋白脱乙酰酶抑制剂

• 批准号: 7140176
• 负责人: VINCENT Collins Ofuka NJAR
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140176
• 关键词: SCID mouse; amidohydrolases; angiogenesis; apoptosis; athymic mouse; biological signal transduction; cell differentiation; cell line; cell proliferation; combination chemotherapy; drug discovery /isolation; enzyme inhibitors; gene expression; hydroxamate; neoplasm /cancer chemotherapy; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; prostate neoplasms; retinoate

DESCRIPTION (provided by applicant): All-trans retinoic acid (ATRA), a derivative of vitamin A (retinol), is required for the appropriate cellular proliferation and differentiation of normal human prostate epithelial cells. Human prostate cancer cells contain much lower levels of ATRA than normal cells. We hypothesize that aberrant metabolism of ATRA and dysregulation of gene expression in prostate tumor cells are related to the abnormal growth properties of the tumor cells. A rationale for using retinoic acid in prostate cancer therapy is further supported by the effectiveness of ATRA in the treatment of acute promyelocytic leukemia (APL). We hypothesize that the efficacy of ATRA can be enhanced if it is administered in combination with retinoic acid metabolism blocking agents (RAMBAs) plus low doses of selective histone deacetylase inhibitors (HDACIs) such as trichostatin A(TSA) or suberoylanilide hydroxamic acid (SAHA). HDACIs will act by sensitizing prostate cancer cells towards ATRA differentiation activity. The discovery of the retinoic acid receptor (RAR)/ADAC complex provides a rationale for combining RAs and HADCIs. The goals of this proposal are to use in vitro cell culture and also mouse xenograft models to ascertain the effectiveness of ATRA, various RAMBAs plus HDACIs in inhibiting the growth and inducing the differentiation of the human prostate cell lines, LNCaP, LAPC-4, PC-3 and DU-145. A second goal of the project is to understand at the molecular level the mechanisms by which the combination treatments result in human prostate tumor cell growth inhibition. These studies may provide a much clearer rationale for new clinical treatments for prostate cancer in humans. If this approach appears successful, we will consider the need for developing novel HDAC inhibitors in the subsequent RO1 proposal on the strengths of our expertise in drug design, discovery and development. The long-term goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen-dependent and androgen independent prostatic cancer. The following specific aims that are proposed should enable us obtain substantial data that may support our hypothesis.

描述（由申请人提供）：全反式视黄酸（ATRA）是维生素A（视黄醇）的衍生物，是正常人前列腺上皮细胞适当的细胞增殖和分化所必需的。人类前列腺癌细胞含有比正常细胞低得多的 ATRA 水平。我们推测前列腺肿瘤细胞中 ATRA 的异常代谢和基因表达失调与肿瘤细胞的异常生长特性有关。 ATRA 在治疗急性早幼粒细胞白血病 (APL) 中的有效性进一步支持了在前列腺癌治疗中使用视黄酸的基本原理。我们假设，如果将 ATRA 与视黄酸代谢阻断剂 (RAMBA) 加上低剂量的选择性组蛋白脱乙酰酶抑制剂 (HDACIs) 如曲古抑菌素 A (TSA) 或辛二酰苯胺异羟肟酸 (SAHA) 联合使用，可以增强 ATRA 的疗效。 。 HDACIs 将通过使前列腺癌细胞对 ATRA 分化活性敏感来发挥作用。视黄酸受体 (RAR)/ADAC 复合物的发现为结合 RA 和 HADCI 提供了理论基础。该提案的目标是使用体外细胞培养和小鼠异种移植模型来确定 ATRA、各种 RAMBA 加 HDACIs 在抑制人类前列腺细胞系、LNCaP、LAPC-4、PC 生长和诱导分化方面的有效性-3和DU-145。该项目的第二个目标是在分子水平上了解联合治疗导致人类前列腺肿瘤细胞生长抑制的机制。这些研究可能为人类前列腺癌的新临床治疗提供更清晰的原理。如果这种方法看起来成功，我们将利用我们在药物设计、发现和开发方面的专业知识优势，在随后的 RO1 提案中考虑开发新型 HDAC 抑制剂的需要。该项目的长期目标是开发具有可能对雄激素依赖性和雄激素非依赖性前列腺癌提供有效抗肿瘤活性特性的化合物。提出的以下具体目标应该使我们能够获得可以支持我们的假设的大量数据。

项目成果

Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro.

设计、合成和评估全反式视黄酸和组蛋白脱乙酰酶抑制剂的新型相互前药（混合药物），在体外增强乳腺癌和前列腺癌细胞的抗癌活性。

• DOI: 10.1021/jm8001839
• 发表时间: 2008-06-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: L. Gediya;A. Kh;elwal;elwal;J. Patel;A. Belosay;G. Sabnis;J. Mehta;P. Purushottamachar;V. Njar
• 通讯作者: V. Njar

Dissecting major signaling pathways in prostate cancer development and progression: Mechanisms and novel therapeutic targets.

剖析前列腺癌发生和进展的主要信号通路：机制和新的治疗靶点。

• 发表时间: 2017
• 作者: Ramalingam, Senthilmurugan;Ramamurthy, Vidya P;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O

Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice.

视黄酸代谢阻断剂 (RAMBA) 对 SCID 小鼠中人前列腺癌细胞和 LNCaP 前列腺肿瘤异种移植物生长的抑制作用。

• 发表时间: 2006-02-27
• 影响因子: 8.8
• 作者: Huynh, C K;Brodie, A M H;Njar, V C O
• 通讯作者: Njar, V C O

Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts.

改善组蛋白脱乙酰酶抑制剂 (HDI)（MS-275 和 CI-994）的合成，以及 HDIs 单独或与 RAMBA 或类视黄醇组合对人 LNCaP 前列腺癌细胞和肿瘤异种移植物生长的抑制作用。

• 发表时间: 2008-03-15
• 影响因子: 3.5
• 作者: Gediya, Lalji K;Belosay, Aashvini;Khandelwal, Aakanksha;Purushottamachar, Puranik;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O

The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

视黄酰胺 VNLG-152 抑制 f-AR/AR-V7 和 MNK-eIF4E 信号通路，从而抑制 EMT 和去势抵抗性前列腺癌异种移植物生长。

• 发表时间: 2018
• 作者: Ramamurthy, Vidya P;Ramalingam, Senthilmurugan;Gediya, Lalji K;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O