Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers.
Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers.
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DOI：
10.1016/j.phrs.2010.11.003
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发表时间：
2011-02
影响因子：
9.3
通讯作者：
Lokeshwar, Bal L.
中科院分区：
文献类型：
--
作者：
Lokeshwar, Bal L.
转移性癌症占癌症死亡率的90%以上。所有癌症的转移都由降解细胞外基质的酶介导。侵袭性肿瘤的特征在于降解ECM的酶和酶的内源性抑制剂之间的不平衡。基质金属蛋白酶（MMP）构成了与癌症转移有关的ECM降解酶的大部分。四环素类药物，特别是其化学修饰的类似物的有效MMP抑制活性，结合其相对良好耐受的药理学特征，导致一些研究人员研究其在各种癌症中的抗癌潜力，包括黑色素瘤、肺癌、乳腺癌和前列腺癌。使用前列腺、乳腺和黑色素瘤的肿瘤测试化学修饰的非抗生素四环素类（CMT或COL）。这些CMT中的一些，特别是CMT-3和CMT-308不仅显著抑制侵袭潜力和MMP活性，而且通过诱导细胞周期停滞和凋亡来抑制细胞增殖。CMT-3和CMT-308在体外和体内抑制肿瘤细胞源性MMPs和诱导凋亡方面明显强于多西环素或米诺环素。CMT-3（Col-3）在前列腺癌的异种移植物和骨转移模型中显示出有效的肿瘤生长抑制。在黑色素瘤和乳腺癌模型中也报告了类似的结果。CMT杀死肿瘤细胞的机制是通过产生羟基自由基（[OH]−），其渗透并使线粒体脱乙酰化，进而激活caspase介导的细胞凋亡。CMT-3治疗大鼠的肿瘤组织分析表明，血管生成减少和细胞凋亡增加;这两者都是CMT作用的机制。这些观察结果导致在人类临床试验中测试CMT-3对几种类型癌症的疗效，并取得了显著的结果，这将在本期的下一章中进行描述。
Metastatic cancers account for more than 90% of cancer mortality. The metastasis of all cancers is critically mediated by enzymes that degrade extracellular matrix. Aggressive tumors are characterized by an imbalance between enzymes that degrade ECM and endogenous inhibitors of the enzymes. Matrix metalloproteinases (MMPs) make up the majority of ECM degrading enzymes implicated in cancer metastasis. The potent MMP inhibitory activities of tetracyclines, especially their chemically modified analogs, combined with their relatively well tolerated pharmacological profile, led several researchers to investigate their anticancer potential in a variety of cancers, including melanoma, lung, breast and prostate cancers. Chemically modified non-antibiotic tetracyclines (CMT, or COL) were tested using tumors of prostate, breast and melanomas. Some of these CMTs, notably, CMT-3 and CMT-308 significantly inhibited not only invasive potential and MMP activity, but also inhibited cell proliferation by inducing cell cycle arrest and apoptosis. CMT-3 and CMT-308 were significantly more potent than doxycycline or minocycline in inhibiting tumor cell-derived MMPs and inducing apoptosis in vitro and in vivo. CMT-3 (Col-3) showed potent inhibition of tumor growth in xenografts and in bone metastatic models of prostate cancer. Similar results were also reported in melanoma and breast cancer models. The mechanism by which CMTs kill tumor cells is via generation of hydroxyl free radicals ([OH]−) which permeate and depolarize mitochondria, which in turn activates caspase mediated apoptosis. Analysis of tumor tissues from CMT-3 treated rats demonstrated reduction in angiogenesis and increase in apoptosis; both emerged as mechanisms of CMT action. These observations led to testing the efficacy of CMT-3 in human clinical trials against several types of cancer with significant outcomes, which are described in the next chapter of this issue.
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影响因子：
2.8
作者：
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通讯作者：
RAO, BR
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作者：
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作者：
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