天然化合物诱导肿瘤细胞程序性坏死的研究进展

程序性坏死是一种新的细胞程序性死亡模式,可抑制多种肿瘤的发生和发展。传统的肿瘤治疗主要以增强细胞凋亡为目标,但许多肿瘤细胞会对化疗药物产生耐药性。因此,发掘克服肿瘤细胞凋亡抗性的天然化合物已成为近年来肿瘤治疗研究的热点。程序性坏死可逆转多种肿瘤耐药,对于抗肿瘤具有重要的临床意义。多种来源于植物、动物或微生物的天然化合物能够通过程序性坏死抑制肿瘤发生和发展。本文论述了近年来天然化合物诱导程序性坏死的研究进展,以期为开发天然化合物成为新型抗肿瘤药物提供理论依据和研究线索。     

TRAIL诱导卵巢癌细胞凋亡的基础研究及临床应用进展

【指示性摘要】肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子（TNF）超家族的成员。它能和死亡受体结合，启动凋亡信号传导，诱导肿瘤细胞凋亡，而对正常组织和细胞没有明显毒性。卵巢癌病人经几个疗程化疗后，常对化疗药产生多药耐药现象，从而使化疗失败，肿瘤复发和转移。TRAIL和化疗药联合应用能逆转卵巢癌细胞的多药耐药性（MDR）。本文就TRAIL诱导卵巢癌细胞凋亡的机制以及对卵巢癌耐药细胞逆转作用做一综述。     

槲皮素逆转肿瘤多药耐药机制的研究进展

恶性肿瘤已成为当今威胁人类健康的重大疾病.目前,肿瘤的治疗主要是以手术为主的综合治疗,其中化疗药物的应用可明显抑制肿瘤生长、改善患者预后,但肿瘤的多药耐药严重阻碍了其治疗效果.槲皮素是广泛存在于植物中、具有生物活性的黄酮类化合物,具有抗肿瘤等多种药理学作用.目前,槲皮素逆转肿瘤多药耐药作用已引起广泛关注.研究发现,其可通过抑制多种耐药相关蛋白、诱导细胞凋亡、抑制热休克蛋白功能、逆转上皮间质转化等作用,从而逆转肿瘤多药耐药.本文主要综述槲皮素逆转肿瘤多药耐药的分子机制及其临床应用前景,以期为逆转肿瘤多药耐药的基础及临床研究提供新思路.     

TRAIL及其受体与卵巢恶性肿瘤的研究进展

肿瘤坏死因子相关的凋亡诱导配体(TNF-related apoptosis-inducing ligand,TRAIL)是最近发现的TNF家族的新成员,TRAIL有两类受体,一类是死亡受体,诱导肿瘤细胞或转化细胞凋亡,另一类是"诱骗"受体,保护正常细胞免遭TRAIL的诱导凋亡作用。卵巢癌患者经几个疗程化疗后,常对化疗药产生多药耐药现象,从而使化疗失败,最终导致肿瘤复发和转移。TRAIL和化疗药联合应用能逆转卵巢癌细胞的多药耐药性(multidrug resistance)。本文就TRAIL、TRAIL受体(TRAILR)表达及TRAIL的凋亡途径等在卵巢恶性肿瘤治疗中的应用做一全面综述。     

TRAIL作用机制及其在肿瘤治疗中的研究

肿瘤坏死因子相关凋亡诱导配体(TRAIL)具有特异性抗肿瘤活性,可通过死亡受体途径及转录因子途径发挥诱导肿瘤细胞凋亡作用.而正常细胞则通过诱骗受体、FLIP及凋亡抑制蛋白来逃逸TRAIL诱导的凋亡.TRAIL与化疗药物、基因治疗联合应用能明显提高肿瘤治疗的靶向性,同时还可以逆转肿瘤细胞对TRAIL的抵抗现象.因此TRAIL作为新型抗肿瘤药物有望应用于临床治疗.     

法尼基转移酶抑制剂在抗肿瘤和逆转肿瘤耐药中的作用

法尼基转移酶抑制剂(FTI)是一类靶向作用于肿瘤细胞增殖、细胞信号转导途径的新药.它通过抑制细胞内包括Ras在内的蛋白法尼基化修饰,诱导细胞凋亡及抑制血管生成从而发挥抗肿瘤作用;通过抑制P糖蛋白(Pgp)的功能来逆转肿瘤的多药耐药(MDR).     

益气养阴方逆转人肺腺癌A549DDP多药耐药机理

目的探讨益气养阴方逆转肿瘤多药耐药的机理。方法 应用血清药理学方法, 采用MTT法及流式细胞术, 探讨益气养阴方逆转肿瘤多药耐药的机理。结果 益气养阴方可以显著的提高DDP对A₅₄₉DDP细胞的增殖抑制作用, 并且二者有显著的协同增效作用, 二者协同具有细胞周期阻滞及诱导A₅₄₉DDP细胞凋亡的作用。结论 逆转A₅₄₉DDP细胞的凋亡抵抗可能是益气养阴方逆转肿瘤多药耐药的机理之一。     

TRAIL及其在血液系统恶性肿瘤中的治疗进展

细胞凋亡（apoptosis）与肿瘤的发生、发展和转移有密切关系,诱导肿瘤细胞凋亡以达到治疗目的是近几年肿瘤治疗的热点之一。肿瘤坏死因子相关的凋亡诱导配体（TNF-related apoptosis-inducing ligand,TRAIL）是新近发现的TNF超家族成员,它能选择性的诱导肿瘤细胞和转化细胞发生凋亡,且与血液系统肿瘤常用的化疗药物具有协同性,还能克服一部分多药耐药现象,而对正常细胞没有显毒性效应,这些特性使TRAIL在血液系统恶性肿瘤的治疗中具有很大的应用前景。本就其结构、功能、作用机制及抗血液病肿瘤研究最新进展作一综述。     

藤黄酸的抗肿瘤机制

目前发现藤黄酸可通过不同机制在多种肿瘤细胞中发挥抗肿瘤作用,包括诱导细胞凋亡,抑制端粒末端转移酶和拓扑异构酶活性,抑制热休克蛋白和通道蛋白表达,抑制肿瘤血管生成和转移,逆转肿瘤多药耐药,提示藤黄酸有望成为新型抗肿瘤药物,且仍需进一步探索其在抗肿瘤领域的价值.     

凋亡抑制因子与肿瘤耐药研究进展

bcl-2家族的抗凋亡成员与凋亡抑制蛋白(IAP)家族过表达可抑制细胞凋亡,使化疗药物产生的凋亡信号成为无效信号,导致细胞凋亡减少而产生耐药。以凋亡抑制基因为靶点的基因治疗,可望成为逆转肿瘤细胞耐药的新策略。现综述凋亡抑制因子的作用机制、功能特点、与肿瘤耐药的关系以及逆转耐药的策略。     

Bypassing cancer drug resistance by activating multiple death pathways--a proposal from the study of circumventing cancer drug resistance by induction of necroptosis

Cancer drug resistance is a complex, dynamic, and "elusive" system rather than merely a matter of some drug-resistant factors. Current pharmacological approaches aim to restore the efficacy of the standard chemotherapy against drug-resistant cancers via reactivating apoptosis and inhibiting drug transporters, simply because the current available anticancer drugs mostly induce apoptosis and many of them are the substrates/inducers of the drug transporters. However, since there are so many different types of defects in apoptotic pathways as well as numerous drug transporters, which could simultaneously contribute to cancer drug resistance, to succeed in the approach is theoretically possible but practically extremely difficult. To circumvent cancer drug resistance is an alternative choice. Since there are multiple death pathways with molecular mechanisms distinct from each other, we previously proposed that the barriers set up in cancer cells to avoid one pathway were not problems for another. Thus, no matter how dynamic, complex, and "elusive" the resistance occurs along one death pathway (e.g., apoptosis), the resistance would be sequestered within this pathway, and would not affect another death pathway with mechanisms distinct from the former, and vice versa, e.g., apoptotic resistant cancers can be sensitive to an induction of a nonapoptotic death. Indeed, we recently demonstrated that the cancer cells resistant to apoptotic inducers such as anthracycline antibiotics, vinca alkaloids, epipodophylotoxins, were sensitive to necroptotic inducers such as shikonin. Therefore, to bypass cancer drug resistance is principally achievable by simultaneously activating multiple death pathways using combined classes of death inducers (apoptosis, autophagy, necroptosis, etc.). Although each class of death inducers has its own action window and limit in killing cancer cells, a rationalized combination of several classes of death inducers that compliment each other would maximize their efficacy while simultaneously minimizing their weakness. Such "mixed bullets" would probably achieve a good therapeutic efficacy by bypassing cancer drug resistance.     

Shikonin Induced Necroptosis via Reactive Oxygen Species in the T-47D Breast Cancer Cell Line

Breast cancer, the most common cancer in the women, is the leading cause of death. Necrotic signalingpathways will enable targeted therapeutic agents to eliminate apoptosis-resistant cancer cells. In the presentstudy, the effect of shikonin on the induction of cell necroptosis or apoptosis was evaluated using the T-47D breastcancer cell line. The cell death modes, caspase-3 and 8 activities and the levels of reactive oxygen species (ROS)were assessed. Cell death mainly occurred through necroptosis. In the presence of Nec-1, caspase-3 mediatedapoptosis was apparent in the shikonin treated cells. Shikonin stimulates ROS generation in the mitochondriaof T-47D cells, which causes necroptosis or apoptosis. Induction of necroptosis, as a backup-programmed celldeath pathway via ROS stimulation, offers a new strategy for the treatment of breast cancer.     

Glycolysis-induced drug resistance in tumors—A response to danger signals?

Tumor cells often switch from mitochondrial oxidative metabolism to glycolytic metabolism even under aerobic conditions. Tumor cell glycolysis is accompanied by several nonenzymatic activities among which induction of drug resistance has important therapeutic implications. In this article, we review the main aspects of glycolysis-induced drug resistance. We discuss the classes of antitumor drugs that are affected and the components of the glycolytic pathway (transporters, enzymes, metabolites) that are involved in the induction of drug resistance. Glycolysis-associated drug resistance occurs in response to stimuli, either cell-autonomous (e.g., oncoproteins) or deriving from the tumor microenvironment (e.g., hypoxia or pseudohypoxia, mechanical cues, etc.). Several mechanisms mediate the induction of drug resistance in response to glycolytic metabolism: inhibition of apoptosis, induction of epithelial-mesenchymal transition, induction of autophagy, inhibition of drug influx and increase of drug efflux. We suggest that drug resistance in response to glycolysis comes into play in presence of qualitative (e.g., expression of embryonic enzyme isoforms, post-translational enzyme modifications) or quantitative (e.g., overexpression of enzymes or overproduction of metabolites) alterations of glycolytic metabolism. We also discern similarities between changes occurring in tumor cells in response to stimuli inducing glycolysis-associated drug resistance and those occurring in cells of the innate immune system in response to danger signals and that have been referred to as danger-associated metabolic modifications. Eventually, we briefly address that also mitochondrial oxidative metabolism may induce drug resistance and discuss the therapeutic implications deriving from the fact that the main energy-generating metabolic pathways may be both at the origin of antitumor drug resistance.     

Naturally-occurring shikonin analogues – A class of necroptotic inducers that circumvent cancer drug resistance

We previously reported that shikonin could circumvent drug resistance mediated by P-gp, Bcl-2 and Bcl-xL, by induction of necroptosis. Here, we show that the naturally-occurring shikonin analogues (deoxyshikonin, acetylshikonin, isobutyrylshikonin, β,β-dimethylacrylshikonin, isovalerylshikonin, α-methyl-n-butylshikonin) could bypass drug resistance mediated by not only P-gp, Bcl-2, and Bcl-xL, but also two additional important drug-resistant factors MRP1 and BCRP1, by induction of necroptosis. The results strengthen the previous findings that necroptotic induction could circumvent a broad spectrum of cancer drug resistance.     

PI3K-Akt信号通路与肿瘤化疗耐药性

磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）信号通路对于细胞增殖、分化、凋亡的调节起关键性作用,与细胞的生理功能和某些疾病的发生关系密切.在许多肿瘤中,PI3K-Akt信号通路的过度激活与肿瘤耐药性的产生也密切相关.体外研究表明,使用化疗药物联合PI3K-Akt信号通路抑制剂,可以显著增强化疗药物作用效果、降低IC50值.因此,PI3K-Akt信号通路已成为一个可以逆转化疗耐药的重要靶点.     

Development of resistance to the atypical retinoid, ST1926, in the lung carcinoma cell line H460 is associated with reduced formation of DNA strand breaks and a defective DNA damage response

Atypical retinoids are potent inducers of apoptosis, but activation of the apoptotic pathway seems to be independent of retinoid receptors. Previous studies with a novel adamantyl retinoid, ST1926, have shown that apoptosis induction is associated with an early genotoxic stress. To better understand the relevance of these events, we have selected a subline of the H460 lung carcinoma cell line resistant to ST1926. Resistant cells exhibited cross-resistance to a related molecule, CD437, but not cross-resistance to agents with different mechanisms of action. In spite of a lack of defects in intracellular drug accumulation, induction of DNA strand breaks in resistant cells required exposure to a substantially higher concentration, which was consistent with the degree of resistance. At drug concentrations causing a similar antiproliferative effect (IC80) and a comparable extent of DNA lesions in sensitive and resistant cells, the apoptotic response was a delayed and less marked event in resistant cells, thus indicating a reduced susceptibility to apoptosis. In spite of recognition of DNA lesions in resistant cells, as supported by phosphorylation of p53 and histone H2AX, resistant cells exhibited no activation of the mitochondrial pathways of apoptosis. Following exposure to equitoxic drug concentrations, only sensitive cells exhibited a typical stress/DNA damage response, with activation of the S-phase checkpoint. The cellular resistance to ST1926 reflects alterations responsible for a reduced generation of DNA lesions and for an enhanced tolerance of the genotoxic stress, resulting in lack of activation of the intrinsic pathway of apoptosis. The defective DNA damage response, accompanied by a reduced susceptibility to apoptosis in resistant cells, provides further support to the involvement of genotoxic stress as a critical event in mediating apoptosis induction by ST1926.     

XIAP is upregulated in HL-60 cells cocultured with stromal cells by direct cell contact

Apoptosis resistance is an important mechanisms of drug resistance mediated by bone marrow stromal cells (BMSCs). BMSCs influence tumor cells survival through several mechanisms including direct cell-cell contact and the effects of soluble factors. In this research we investigated the role of X-linked inhibitor of apoptosis protein (XIAP) in the apoptosis resistance mediated by stromal cells in HL-60 cells and the signaling pathway involved. We found that bone marrow stromal-derived soluble factors and direct cell contact both prevented apoptosis of HL-60 cells. XIAP is upregulated by direct cell contact but not by soluble factors. Phosphatidylinositol 3-kinase (PI3K) and Akt were activated and LY294002 downregulated XIAP and increased apoptosis in HL-60 cells co-cultured with BMSCs. The results indicated that PI3K/Akt/XIAP is an important pathway involved in the apoptosis resistance of HL-60 cells co-cultured with BMSCs by direct cell contact. Inhibition of this signaling pathway may provide a new therapeutic strategy for acute myeloid leukemia treatment.     

Drug-resistance in human melanoma

Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.