在治疗肿瘤领域中组蛋白去乙酰化酶抑制剂的研究进展

近年来在治疗肿瘤领域中组蛋白去乙酰化酶（HDAC）抑制剂的研究已成为热点。组蛋白乙酰化转移酶（HAT）与组蛋白去乙酰化酶（HDAC）之间保持的动态平衡调控着有序的基因表达, HDAC表达过度造成乙酰化的失衡会形成肿瘤,而HDAC抑制剂可诱导肿瘤细胞分化、细胞周期停滞和凋亡,抑制肿瘤的生成。HDAC抑制剂是很有前途的新型癌症靶向治疗药物。本文将重点阐述HDAC抑制剂的作用机制以及在肿瘤治疗领域中的研究进展。     

乳腺癌细胞耐药性的分子机理

近日,来自Norris Cotton综合癌症研究中心的研究人员通过研究开发了一种治疗ERBB2(人类表皮生长因子受体Ⅱ)阳性乳腺癌的新型疗法,该类乳腺癌通常会对疗法产生强烈的耐药性,相关研究刊登于国际杂志Cell Cycle上,该研究为揭示新型的癌症耐药机制提供了一定的线索。研究者Kurokawa教授表示,目前大约有25%的乳腺癌会发生过表达,而且依赖于ERBB2来生存。当前的疗法往往是通过利用靶向药物,如曲妥珠单抗或拉帕替尼,特异性地抑制ERBB2,但最终这些疗法会随着癌细胞产生耐药性而     

白血病药物达沙替尼有望治疗皮肤癌和其他癌症

近日,美国芝加哥洛约拉大学医学院的研究显示,一种治疗白血病的药物达沙替尼显示出对皮肤癌、乳腺癌以及一些其他类型的癌症有治疗作用。 达沙替尼通过抑制那些肆意生长的肿瘤细胞来治疗白血病。但是研究人员发现,使用达沙替尼治疗其他类型的肿瘤,它可以通过另外一种不同的作用机制来治疗肿瘤：使肿瘤细胞聚集在一起,防止肿瘤细胞迁移。     

HER2阳性乳腺癌靶向治疗药物的临床研究进展

乳腺癌已成为全球最常见的癌症,人表皮生长因子受体2（HER2）阳性乳腺癌恶性程度较高,早期易复发和转移,总体预后较差。HER2阳性乳腺癌的治疗因靶向药物的不断问世而呈现更多可能,这类药物包括单克隆抗体（曲妥珠单抗、帕妥珠单抗）、酪氨酸激酶抑制剂（奈拉替尼、拉帕替尼、吡咯替尼、图卡替尼）、抗体药物偶联物（T-DM1、DS-8201）。对HER2阳性乳腺癌靶向治疗药物的最新临床试验结果进行综述,以期为该类乳腺癌的临床用药提供参考。     

反义寡核苷酸治疗乳腺癌研究进展(英文)

乳腺癌是一类与多基因相关的恶性肿瘤,有些痛基因如HER-2(c-erbB-2,Neu),bcl-2/6cl-xL,蛋白激酶A(PKA),运铁蛋白受体基因(TfR gene)等的过度表达对乳腺癌的预后有明显影响,有证据表明抑制上述过度表达基因能明显改善乳腺痛的治疗效果。近年,反义治疗这种能抑制特定癌基因过度表达的有效手段被应用于乳腺癌的治疗。研究表明,在多数情况下,反义寡核苷酸(ON)能在mRNA或蛋白水平抑制目的基因的表达,有些反义ON在体和离体对乳腺癌细胞系或动物乳腺癌异植肿瘤均显示出令人鼓舞的治疗效果。此外,反义ON与常规化疗药物合用也能产生协同的抗肿瘤作用。反义ON与化疗药物合用可能在不远的将来是治疗乳腺癌的最佳方法之一。     

两种不同品牌恩替卡韦治疗慢性乙型肝炎成本分析

慢性乙型肝炎(CHB)是慢性疾病,抗病毒治疗用药时间较长,患者所需费用较高,选择安全、有效、经济的药物治疗,对减轻患者经济负担,增加患者用药的依从性具有一定的现实意义.恩替卡韦是鸟嘌呤核苷类似物,在体内经磷酸化后转化为具有活性的三磷酸盐形式,抑制病毒多聚酶的活性,从而抑制乙型肝炎病毒(HBV)复制.文中通过对两种不同品牌恩替卡韦治疗CHB的成本进行分析,为患者选择药品提供参考.     

基于组蛋白去乙酰化酶设计的多靶点抗肿瘤药物研究进展

肿瘤的发生是一个多因子、多步骤的复杂过程。多靶点抗肿瘤药物能同时作用于肿瘤发生的多个疾病通路,比单靶点抗肿瘤药物有更好的治疗效果。研究显示,组蛋白去乙酰化酶(histone deacetylase,HDACs)在多种肿瘤细胞中过度表达,是肿瘤发生的关键靶点,因此以抑制HDACs为基础设计兼顾作用于其他靶点的多靶点抗肿瘤药物,成为重要的研究方向。目前已有5个HDAC抑制剂被批准上市用于治疗皮肤T细胞淋巴瘤、多发性骨髓瘤和外周T细胞淋巴瘤,还有十几个HDAC抑制剂正处于不同的临床研究阶段用于治疗各种癌症。基于此,本文综述了近年来此类多靶点分子的设计和生物活性研究,以期为进一步研发此类多靶点药物提供参考。     

拉帕替尼在欧盟获准与卡培他滨联用治疗乳腺癌

最近，欧委会批准拉帕替尼（lapatinib，Tyverb）在所有27个欧盟成员国有条件地上市使用，即该药可与卡培他滨联用治疗具ErbB2（HER2）过度表达的晚期或转移性乳腺癌患者，这些患者为先前经蒽环类和紫杉烷类等药物治疗后以及其中转移性癌症患者使用曲妥珠单抗治疗后病情仍出现恶化者。拉帕替尼是一种口服小分子药物，具有新的作用机制，可抑制2种受体蛋白——ErbB1和ErB2受体中酪氨酸激酶成分，而这些受体的信号转导是肿瘤生长和增殖的诱因。     

广角

肺癌药能防治乳腺癌美国一项动物实验显示,一种用于治疗肺癌的药物吉非替尼能够对乳腺癌起到防治作用。据最近一期美国《全国癌症研究所》杂志报道,美国贝勒医科大学的研究人员首先使用基因技术培养出易患乳腺癌的实验鼠,然后让实验组老鼠服用吉非替尼,对照组老鼠只服用安慰剂。结果,对照组老鼠在230天后出现乳腺癌症状,而服用吉非替尼的老鼠则在310天后才发病,比前者推迟了80天。研究人员说,所有对照组的老鼠在实验最后都患上了乳腺癌,而只有25%的服用吉非替尼的实验组老鼠出现了癌症症状。点评:癌症发病时间的推迟对人类来说具有十分重要…     

Karus研发HDAC-6抑制剂在新领域中的应用

Karus Therapeutics有限公司是一家致力于研发治疗炎症和癌症的分子靶向药物的公司,该公司近日宣布,它已把其组蛋白脱乙酰基酶药物（HDAC）发现计划扩大到将选择性抑制组蛋白脱乙酰基酶-6（HDAC-6）的小分子包括在内,HDAC-6作为治疗免疫炎症性紊乱疾病靶点的重要性日渐显现。     

Anti-Cancer Effect of IN-2001 in T47D Human Breast Cancer

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents. In recent years, a number of structurally diverse HDAC inhibitors have been identified and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. However, the underlying molecular mechanisms remain unclear. This study aimed at investigating the anti-tumor activity of various HDAC inhibitors, IN-2001, using T47D human breast cancer cells. Moreover, the possible mechanism by which HDAC inhibitors exhibit anti-tumor activity was also explored. In estrogen receptor positive T47D cells, IN-2001, HDAC inhibitor showed anti-proliferative effects in dose-and time-dependent manner. In T47D human breast cancer cells showed anti-tumor activity of IN-2001 and the growth inhibitory effects of IN-2001 were related to the cell cycle arrest and induction of apoptosis. Flow cytometry studies revealed that IN-2001 showed accumulation of cells at G₂/M phase. At the same time, IN-2001 treatment time-dependently increased sub-G₁ population, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with induction of cdk inhibitor expression. In T47D cells, IN-2001 as well as other HDAC inhibitors treatment significantly increased p21^WAF1 and p27^KIP1 expression. In addition, thymidylate synthase, an essential enzyme for DNA replication and repair, was down-regulated by IN-2001 and other HDAC inhibitors in the T47D human breast cancer cells. In summary, IN-2001 with a higher potency than other HDAC inhibitors induced growth inhibition, cell cycle arrest, and eventual apoptosis in human breast cancer possibly through modulation of cell cycle and apoptosis regulatory proteins, such as cdk inhibitors, cyclins, and thymidylate synthase.     

A new synthetic HDAC inhibitor, MHY218, induces apoptosis or autophagy-related cell death in tamoxifen-resistant MCF-7 breast cancer cells

Acquired resistance to tamoxifen (Tam) is a critical problem in breast cancer therapy. Therefore, new potential strategies for Tam-resistant breast cancer are needed recently. In this study, we synthesized a novel histone deacetylase (HDAC) inhibitor, MHY218, for the development of potent inhibitors of HDAC and evaluated its biological activities by monitoring the anticancer effects in Tam-resistant MCF-7 (TAMR/MCF-7) cells via in vitro and in vivo studies. MHY218 significantly inhibited the proliferation of TAMR/MCF-7 cells in a dose-dependent manner. The total HDAC enzyme activity was significantly inhibited, corresponding with inhibition of acetylated H3 and H4 expression in TAMR/MCF-7 cells. HDAC1, 4, and 6 expression levels were decreased in response to MHY218 treatment. Cell cycle analysis indicated that MHY218 induced G2/M phase cell cycle arrest. As expected, apoptotic cell death was observed in response to MHY218 treatment. Interestingly, levels of beclin-1 and LC3-II, the markers of autophagy, were increased in TAMR/MCF-7 cells treated with MHY218. The efficacy of MHY218 was also compared with that of SAHA in vivo in a xenograft model of nude mice bearing a TAMR/MCF-7 cells. MHY218 (10 mg/kg, twice a week for 21 days) completely inhibited tumor growth and MHY218 markedly inhibited the expression of proliferative cell nuclear antigen (PCNA) in tumor tissue. These results indicate that MHY218 can induce caspase-independent autophagic cell death rather than apoptotic cell death. The MHY218-induced autophagic cell death could be a new strategy in the treatment of Tam-resistant human breast cancer.     

PET imaging of steroid receptor expression in breast and prostate cancer

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.     

Anti-Cancer Effect of IN-2001 in MDA-MB-231 Human Breast Cancer

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity (IC₅₀ = 0.585 nM) in MDA-MB-231 human breast cancer cells. IN-2001 caused a significant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231 human breast cancer cells. Cell cycle analysis revealed that the gowth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at G₀/G₁ and/or G₂/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors p21^WAF1 and p27^KIP1 cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these findings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.