白花丹素抗肿瘤作用机制的研究进展

恶性肿瘤一直是生物医学中的难题，利用放射疗法或化学疗法治疗肿瘤常会引发如呕吐、恶心等不良反应。因此，寻找安全有效治疗肿瘤的替代药物源非常重要。白花丹素(plumbagin, PLB)是从中草药白花丹根部提取出来的一种生物活性化合物，在肿瘤治疗中具有重要作用，并且有较好的抗癌活性。因此，本文将从肿瘤细胞的增殖、凋亡、转移和侵袭、血管生成、铁死亡过程以及化疗敏感性等六个方面对白花丹素的抗肿瘤作用及相关分子机制的研究进行综述，以期为基于白花丹素的抗肿瘤药物研发和临床应用提供科学参考。     

植物次生代谢产物及其衍生物的抗肿瘤成药研究进展

面对严重威胁健康的肿瘤,人类从未间断过抗肿瘤药物的研发。纵观历史,从非选择性的化疗药物,到特异性阻断驱动致癌基因的靶向药物,直到今天以患者为中心的个体化肿瘤治疗,抗癌药物迅猛发展,成为提高肿瘤患者生存率的重要治疗手段。然而,由于大多数抗癌药物存在难以克服的短期耐药及毒副作用等问题,严重影响临床治疗效果。近年,筛选植物来源的天然提取物及其次生代谢产物的抗癌作用,倍受关注并取得令人瞩目的进展,包括临床广泛应用的紫杉醇、长春新碱、依托泊苷及喜树碱等。总结植物的抗肿瘤活性成分、筛选方法、潜在作用机制及临床应用等国内外研究现状,旨在为植物来源的抗肿瘤药物的深入研发提供参考。     

紫草素通过下调HPV E6/E7蛋白表达抑制宫颈癌Caski细胞增殖

宫颈癌是发展中国家癌症死亡的主要癌症之一,也是最常见的女性生殖系统肿瘤,它与病毒相关且其主要是由人乳头瘤病毒(human papillomavirus, HPV)感染引起的癌症。紫草素在控制细胞凋亡、坏死性凋亡和免疫原性细胞死亡中的重要作用而被证明具有抗肿瘤活性,且与肿瘤细胞生长和转移密切相关,但是缺乏相应的机理和机制研究。因此本实验就通过用不同浓度紫草素处理宫颈癌细胞来研究紫草素的作用机理。结果表明,紫草素能够通过下调HPV E6/E7蛋白的表达,从而提高抑癌因子P53的活性,以促进宫颈癌细胞凋亡的发生。且与前人的研究相同的是,HPV E6/E7蛋白低表达不利于宫颈癌细胞的增殖和迁移。因此,这些结果充分证实了紫草素能有效地抑制宫颈癌细胞增殖和迁移,以及促进癌细胞凋亡的作用。本实验的研究结果探索了紫草素抑制肿瘤的机制,并为宫颈癌治疗的新方法提供了新的思路以及为后续机制的研究提供了参考和理论依据。     

抗癌肽的作用机制研究进展

近年来癌症的发生率和死亡率呈现逐渐上升的趋势,是威胁人类生命的主要疾病之一。抗癌肽(Anticancer peptides,ACPs)即具有抗肿瘤活性的生物活性肽,其广泛存在于多种生物体内,包括哺乳动物、两栖类动物、昆虫、植物和微生物等。抗癌肽在治疗肿瘤方面具有众多优势,如分子量低、结构简单、高抗癌活性、高选择性、较少的副作用、多种给药方式、不易引起多重耐药性等。文中结合本课题组相关工作,归纳了目前所发现的抗癌肽的作用机制,以期为新型肽类抗肿瘤药物的研发提供一定的方向。     

根癌农杆菌转化紫草的研究

紫草 (ＬｉｔｈｏｓｐｅｒｍｕｍｅｒｙｔｈｒｏｒｈｉｚｏｎＳｉｅｂ .ｅｔＺｕｃｃ)是传统中药。其根部含有萘醌类化合物—紫草素及其衍生物 ,具有显著的抗菌、抗炎、抗癌以及促进伤口愈合等生理活性。紫草素同时也是一种名贵化妆品染料。科学家对紫草的研究兴趣是基于其资源的缺乏及紫草植物本身所具有的一些特点 ;如 :紫草素及其衍生物的颜色特性可凭借肉眼观察 ,紫草素及其衍生物只在紫草的根部积累 ,紫草素合成的次生代谢途径受多种酶和外界条件 (光照 ,营养等 )的调节等。紫草细胞培养 (Ｆｕｊｉｔａ等 ,1983;叶和春等 ,1991)可以产…     

抗体偶联药物的研究进展与质量控制

抗体偶联药物（antibody-drug conjugates,ADC）因其良好的靶向性及抗癌活性目前已成为抗肿瘤抗体药物研发的新热点和重要趋势,受到越来越多的关注。ADC药物由单克隆抗体、高效应的细胞毒性物质以及连接臂三部分组成,它将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题。与传统单抗药物相比,因其结构复杂,ADC药物质量属性分析方法的建立具有更大的难度和特殊性。对抗体偶联药物的研发现状、质量属性分析方法和挑战以及质量控制要点进行了简要介绍,为ADC药物的研究和质量控制提供参考。     

蓼科植物抗肿瘤研究进展

蓼科植物中的多种化学成分都有抗肿瘤作用,抗肿瘤机制比较多样,有广阔的研究及开发前景。本文从蓼科植物抑制癌细胞生长和分裂、抑制癌细胞的侵袭和转移、诱导癌细胞凋亡、抑制癌细胞信号的转导、降低癌细胞的抗药性、直接杀伤癌细胞、预防肿瘤作用等七个方面对蓼科植物抗肿瘤方面的研究进行了综述,以期待为更深入研究本科植物抗肿瘤机制及开发抗肿瘤药物提供参考。     

双刃剑:自噬与肿瘤发生发展的关系及相关靶点小分子药物研究进展

自噬是哺乳动物细胞内重要且复杂的生理活动,同样影响着肿瘤的发生与进展.随着抗肿瘤药物的广泛使用,肿瘤耐药问题日益突出,影响患者预后.多年研究显示,肿瘤自噬与耐药密切相关.目前,已有越来越多的自噬相关小分子药物被用来调节肿瘤自噬活动,以求其能被广泛运用于抗癌方案之中.该文将针对自噬在癌症发生发展过程中的分子机制及相关小分...     

高良姜素通过PTEN/AKT信号通路抑制乳腺癌发展并增加曲妥珠单抗抗肿瘤活性

本文旨在研究中药高良姜素对人乳腺癌的治疗作用,对乳腺癌治疗靶向药物曲妥珠单抗抗癌活性影响及其机制.通过建立乳腺癌肿瘤移植模型,研究高良姜素、曲妥珠单抗以及联合用药后的乳腺癌肿瘤进展,试验结束后获取组织进行免疫化学和免疫荧光分析,并进一步检测不同药物处理对细胞侵袭和转移能力的影响,通过TUNNEL法进行细胞凋亡分析,通过...     

姜黄素与消化系统肿瘤的研究进展

姜黄素是一种疏水多酚,从姜黄中提取的姜黄磺胺类草药。半个世纪以来大量的研究表明姜黄素在体外及体内显示了各种诸如抗炎、细胞活素的释放、抗氧化、免疫调节、促进凋亡以及抗血管生成的特性。姜黄素同样也被证明是耐药性和放疗不敏感性的调解者。同样,在各种临床试验研究中证明了姜黄素抗肿瘤的作用,本文就姜黄素在消化系统肿瘤中的抗肿瘤机制做一综述。     

Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

Purpose

Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance.

Experimental Design

Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling.

Results

After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of βII-tubulin, which physically interacted with shikonin.

Conclusion

Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.     

Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres

Although cancer stem-like cells (CSCs) are rare, they can enter a non-proliferative or dormant state and resist therapy. Furthermore, quiescent CSCs are responsible for metastases that can appear after curative surgical treatment of a primary tumor. Because of drug resistance of CSCs, the development of novel therapies is urgently required that specifically target CSCs.PurposeThe aim of the present study was to investigate the potential of a panel of natural products and derivatives to inhibit CSC-enriched mammospheres of MCF-7 breast cancer cells.MethodsCD44^high/CD24^low cells were identified by flow cytometry and maintained as mammospheres. As a control, we used two clinically established anticancer drugs (5-fluorouracil and docetaxel). A panel of natural products, shikonin, two cajanin stilbene acid (CSA) derivatives and artesunate were tested by resazurin assay on CSC-enriched mammospheres and MCF-7 monolayer cells. Besides, cellular shikonin uptake experiments were performed by flow cytometry.ResultsWe found two CSA derivatives (Nos. 6 and 19) to be active cancer stem-like MCF-7 mammospheres. Especially, CSA derivative No. 19 clearly showed collateral sensitivity in mammospheres compared to monolayer cells.ConclusionPhytochemicals which provoke collateral sensitivity in cancer-stem like cells are worth more detailed investigations in the future, since there is a great potential for improved chemotherapy to eradicate tumors and prolong cancer patients’ survival times.     

A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress

BackgroundNSCLC is the major type of lung cancer and the survival rates of NSCLC patients remain low. AZD9291 is a third-generation EGFR-TKI and approved to treat NSCLC patients harboring EGFR T790M mutation and common targetable activating EGFR mutations, but it has a limited effect for wtEGFR NSCLC.PurposeThe current study investigated whether shikonin could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells.MethodsSRB and colony formation assay were used to detect the proliferation of NSCLC cells, propidium iodide staining was performed to detect the apoptosis, ROS was analyzed using DCFH-DA staining, and western blot was used to detect the expression of indicated proteins.ResultsWe demonstrated that shikonin, a natural ROS inducer, could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. In addition, shikonin increased AZD9291-induced apoptosis accompanying with the generation of ROS and activation of ER stress. Furthermore, ROS inhibition by NAC or GSH reversed the apoptosis induced by shikonin plus AZD9291, and recovered the ER stress activated by combination treatment, indicating that ROS mediated ER stress played a vital role in this combination therapy. Moreover, shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress.ConclusionOur study suggests that combining shikonin with AZD9291 is a promising therapeutic strategy for treating wtEGFR NSCLC patients.     

Shikonin inhibits proliferation of melanoma cells by MAPK pathway-mediated induction of apoptosis

Shikonin, a natural product isolated from the roots of Lithospermum erythrorhizon, exhibits pharmacological effects against inflammation, ulcers, infections, and tumors. In the present study, we aimed to investigate the antitumor effects of shikonin on the human melanoma cell line, A375SM, and in an in vivo mouse xenograft model. We examined the anticancer effects of shikonin by in vitro experiments (MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, 4′,6-diamidino-2-phenylindole (DAPI) stain, annexin V/ propidium iodide (PI) stain, and protein analysis of apoptosis and mitogen-activated protein kinase (MAPK) pathways). Further, the anticancer effect in vivo was confirmed through a xenograft model. Our results showed that shikonin inhibited the proliferation of melanoma cells in a dose-dependent manner. In addition, shikonin significantly increased nucleus and chromatin condensation and early/late apoptosis. Shikonin also increased the pro-apoptotic proteins and decreased the anti-apoptotic proteins. Additionally, shikonin was overexpressed in MAPK pathways. Investigation of the effects of shikonin in a mouse xenograft model not only showed decreased A375SM tumor volume but also increased apoptosis as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Furthermore, pathologic changes were not observed in the liver and kidney of mice. Collectively, the study indicated that shikonin inhibited the proliferation of the human melanoma cells by inducing apoptosis, mediated by MAPK pathway and that it is a potential candidate for an anticancer drug against melanoma cancer.     

Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells

Shikonin, a major active component of the Chinese herbal plant Lithospermum erythrorhizon, has been applied for centuries in traditional Chinese medicine. Although shikonin demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of shikonin have not been fully defined. We report here that shikonin may interact with the cytosolic thioredoxin reductase (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme with a C-terminal -Gly-Cys-Sec-Gly active site, to induce reactive oxygen species (ROS)-mediated apoptosis in human promyelocytic leukemia HL-60 cells. Shikonin primarily targets the Sec residue in TrxR1 to inhibit its physiological function, but further shifts the enzyme to an NADPH oxidase to generate superoxide anions, which leads to accumulation of ROS and collapse of the intracellular redox balance. Importantly, overexpression of functional TrxR1 attenuates the cytotoxicity of shikonin, whereas knockdown of TrxR1 sensitizes cells to shikonin treatment. Targeting TrxR1 with shikonin thus discloses a previously unrecognized mechanism underlying the biological activity of shikonin and provides an in-depth insight into the action of shikonin in the treatment of cancer.     

Combination of attenuated Salmonella carrying PD-1 siRNA with nifuroxazide for colon cancer therapy

Colon cancer is a member of malignant tumors in the digestive system. Traditional treatment strategies are ineffective and improving the treatment of colon cancer is an urgent need. Targeting programmed cell death-1 (PD-1) by monoclonal antibodies has shown some therapeutic effectiveness and has advantages. Additionally, the Stat3 inhibitor nifuroxazide was employed to promote the antitumor activity. Here, we hypothesized that combining nifuroxazide with PD-1 small interfering RNA carried by attenuated Salmonella would exert a synergistic antitumor effect on colon cancer. Indeed, treatment with this combination effectively inhibited the development of colon cancer in mice and improved the survival rate. These two novel anticancer agents worked synergistically to elicit potent antitumor immunity and achieve improved therapeutic efficacy. The underlying mechanisms are mainly involved with immune regulation and cell apoptosis. This study provides a previous framework for combining this Stat3 inhibitor with RNAi designed to block immune checkpoint signaling for cancer therapy.     

Small molecules baicalein and cinnamaldehyde are potentiators of measles virus-induced breast cancer oncolysis

BackgroundAlthough the breast cancer mortality has slowed down from 2008 to 2017, breast cancer incidence rate continues to rise and thus, new and/or improved treatments are highly needed. Among them, oncolytic virotherapy which has the ability of facilitating the antitumor adaptive immunity, appears as a promising anticancer therapy. Oncolytic measles virus (MV) is particularly suitable for targeting breast cancer due to the upregulation of MV's receptor nectin-4. Nonetheless, with limited clinical success currently, ways of boosting MV-induced breast cancer oncolysis are therefore necessary. Oncolytic virotherapy alone and combined with chemotherapeutic drugs are two strategic areas with intensive development for the search of anticancer drugs. Considering that baicalein (BAI) and cinnamaldehyde (CIN) have demonstrated antitumor properties against multiple cancers including breast cancer, they could be good partners for MV-based oncolytic virotherapy.PurposeTo assess the in vitro effect of BAI and CIN with MV and assess their combination effects.MethodsWe examined the combinatorial cytotoxic effect of oncolytic MV and BAI or CIN on MCF-7 breast cancer cells. Potential anti-MV activities of the phytochemicals were first investigated in vitro to determine the optimal combination model. Synergism of MV and BAI or CIN was then evaluated in vitro by calculating the combination indices. Finally, cell cycle analysis and apoptosis assays were performed to confirm the mechanism of synergism.ResultsOverall, the viral sensitization combination modality using oncolytic MV to first infect MCF-7 breast cancer cells followed by drug treatment with BAI or CIN was found to produce significantly enhanced tumor killing. Further mechanistic studies showed that the combinations ‘MV-BAI’ and ‘MV-CIN’ display synergistic anti-breast cancer effect, mediated by elevated apoptosis.ConclusionWe demonstrated, for the first time, effective combination of oncolytic MV with BAI or CIN that could be further explored and potentially developed into novel therapeutic strategies targeting nectin-4-marked breast cancer cells.     

Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells

IntroductionSeveral cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown.MethodsThis study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis.ResultsWe demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a.ConclusionIn keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.     

Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action

BackgroundEpidemiological studies has revealed that a diet rich in fruits and vegetables could lower the risk of certain cancers. In this setting, natural polyphenols are potent anticancer bioactive compounds to overcome the non-target specificity, undesirable cytotoxicity and high cost of treatment cancer chemotherapy.PurposeThe review focuses on diverse classifications of the chemical diversity of dietary polyphenol and their molecular targets, modes of action, as well as preclinical and clinical applications in cancer prevention.ResultsThe dietary polyphenols exhibit chemo-preventive activity through modulation of apoptosis, autophagy, cell cycle progression, inflammation, invasion and metastasis. Polyphenols possess strong antioxidant activity and control multiple molecular events through activation of tumor suppressor genes and inhibition of oncogenes involved in carcinogenesis. Numerous in vitro and in vivo studies have evidenced that these dietary phytochemicals regulate critical molecular targets and pathways to limit cancer initiation and progression. Moreover, natural polyphenols act synergistically with existing clinically approved drugs. The improved anticancer activity of combinations of polyphenols and anticancer drugs represents a promising perspective for clinical applications against many human cancers.ConclusionThe anticancer properties exhibited by dietary polyphenols are mainly attributed to their anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic and autophagic effects. Hence, regular consumption of dietary polyphenols as food or food additives or adjuvants can be a promising tactic to preclude adjournment or cancer therapy.     

Design and Synthesis of Fluoroacylshikonin as an Anticancer Agent

A series of shikonin derivatives, selectively acylated by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds are reported for the first time. Among all the compounds tested, compound S7 showed the most potent anticancer activity against B16‐F10 (malignant melanoma cells), MG63 (human osteosarcoma cells), and A549 (lung cancer cells) with IC₅₀ 0.39 ± 0.01, 0.72 ± 0.04 and 0.58 ± 0.02 µmol/L. Docking simulation of compound S7 was carried out to position S7 into a tubulin active site to determine the probable binding conformation. All the results suggested that compound S7 may be a potential anticancer agent. Chirality 25:757–762, 2013. © 2013 Wiley Periodicals, Inc.