喹唑啉类化合物抗肿瘤活性的筛选及Erlotinib抗肿瘤新机制的研究
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摘要
肿瘤的治疗一直是一个世界性的难题。随着人们对肿瘤细胞信号转导途径知识的不断增加,针对肿瘤的特异性分子靶点设计抗肿瘤药物越来越受到关注。加上晶体衍射技术、组合化学、分子模型、高通量筛选技术以及计算机化学的发展,靶向性药物日新月异,为肿瘤的治疗提供了新策略。基于结构和作用机制的药物设计已成为当前发展抗肿瘤药物的主流方式。
表皮生长因子受体(epidermal growth factor receptor,EGFR)是ErbB家族的成员之一,具有酪氨酸激酶(tyrosine kinase,TK)活性,是一种重要的跨膜受体。EGFR信号通路关乎细胞的迁移、黏附、增殖、分化、凋亡,与肿瘤的形成和恶化密切相关。从1984年EGFR基因首次被克隆,20多年来的研究显示,EGFR是肿瘤治疗中一个富有前景的靶分子。近年来对喹唑啉类化合物生物活性的分析可见,该类化合物是一类具有多重药理作用的小分子化合物,其对EGFR-TK活性的抑制作用尤为突出。埃罗替尼(Erlotinib)是Genentech公司、Roche公司和OSI公司联合开发的一种小分子EGFR-TK抑制剂(EGFR-TK inhibitor,EGFR-TKI),属喹唑啉类化合物。其主要作用机制为竞争性抑制三磷酸腺苷(adenosine-triphosphate,ATP)与EGFR胞内催化位点的结合,降低EGFR的自身磷酸化作用,从而导致细胞生长停滞并走向凋亡。另有研究发现,Erlotinib可诱导细胞周期抑制蛋白p27~(KIP1)的表达,使细胞周期阻滞于G1期。
虽然对靶向EGFR的抗肿瘤药物的研究已取得许多具有里程碑意义的成绩,但仍有很多问题亟待解决:如何使此类药物只作用于肿瘤细胞的拟定靶点,而不作用于正常细胞的相同靶点;在联合疗法中,如何进行疗效相加或协同的选择等。这些都阻碍了靶向EGFR的抗肿瘤药物的临床应用。因此,关于靶向EGFR的抗肿瘤药物的作用机制和适用范围等的研究具有深远的意义。
本文工作第一部分是在离体水平初步筛选系列喹唑啉类新化合物的抗肿瘤作用并研究其对TK活性的影响;第二部分以Erlotinib为代表,探讨喹唑啉类化合物抗肿瘤作用的新机制,旨在为肿瘤的分子靶向治疗提供新的候选化合物,并为将喹唑啉类化合物发展为更有效的抗肿瘤药物积累必要的学术与实验基础。
第一部分喹唑啉类化合物抗肿瘤活性的筛选
目的:筛选系列喹唑啉类新化合物的抗肿瘤作用并研究其对TK活性的影响。
方法:MTT法测定肿瘤细胞活力;酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)试剂盒测定TK活性。
结果:与Gefitinib、Erlotinib相比,GⅠ系列2～6号化合物,GⅡ系列2～5号化合物,GⅣ系列2、6号化合物,BⅠ系列2～8号化合物,BⅡ系列2、5、7、8号化合物明显抑制肿瘤细胞增殖,其中BⅠ系列2～8号化合物抑制效应明显强于同浓度阳性药物,最高抑制率超过90%。ELISA法测定21种初筛有效的新化合物对细胞TK活性的影响,结果显示,GⅠ系列5、6号化合物,GⅡ系列4、5号化合物,BⅠ系列8号化合物,BⅡ系列5、7号化合物可显著抑制TK活性。
结论:七个系列共计44种新化合物中,GⅠ系列2～6号化合物,GⅡ系列2～5号化合物,GⅣ系列2、6号化合物,BⅠ系列2～8号化合物,BⅡ系列2、5、7、8号化合物能够明显抑制肿瘤细胞株的增殖,体外显示良好的生物抑瘤作用,BⅠ系列2～8号化合物作用明显强于同浓度的Gefitinib、Erlotinib和其他新化合物;其中GⅠ系列5、6号化合物,GⅡ系列4、5号化合物,BⅠ系列8号化合物,BⅡ系列5、7号化合物对细胞TK活性的抑制效应显著(P＜0.05),具有良好的分子靶向性,有望成为肿瘤靶向治疗的候选化合物。
第二部分Erlotinib抗肿瘤新机制的研究
目的:探讨Erlotinib抗肿瘤效应的新机制。
方法:hoechst 33342荧光染色测定细胞凋亡;DCFH-DA荧光探针检测胞内活性氧簇(reactive oxygen species,ROS);提取A549细胞线粒体,氧电极法测定线粒体呼吸功能;DHE荧光探针检测胞内超氧化物阴离子(O_2~-);RT-PCR法测定NADPH氧化酶催化亚基gp91的表达变化;MTT法测定细胞活力;JC-1荧光探针检测线粒体膜电位(mitochondrial membrane potential,△Ψ_m);western-blotting法测定细胞色素C,凋亡诱导因子(apoptosis-inducing factor,AIF),c-Jun NH_2端激酶(c-Jun NH_2-terminal kinase,JNK),磷酸化JNK(p-JNK)的表达变化。
结果:1)Erlotinib呈浓度依赖性诱导A549细胞的凋亡。2)Erlotinib作用30 min呈浓度依赖性增加A549细胞胞内的ROS水平。3)Erlotinib呈浓度依赖性增加A549细胞的线粒体呼吸控制率(respiratory control ratio,RCR),Erlotinib(10μM)可降低Ⅳ态呼吸。4)Erlotinib作用30 min呈浓度依赖性促进A549细胞O_2~-的产生并增加A549细胞NADPH氧化酶催化亚基gp91的mRNA水平。5)抗氧化剂N-乙酰半胱氨酸(N-acetyl-L-cysteine,NAC)(1 mM)可抑制Erlotinib(10μM)降低细胞活力的作用。6)Erlotinib作用24 h呈浓度依赖性降低A549细胞的△Ψ_m,并促进A549细胞线粒体内细胞色素C和AIF的释放。7)Erlotinib作用24 h呈浓度依赖性促进A549细胞JNK的磷酸化。
结论:Erlotinib可通过增加ROS的产生,活化JNK,激活线粒体凋亡通路而发挥抗肿瘤作用。
本文研究工作表明喹唑啉类化合物经优化设计后,可形成活性较高的新化合物。它们不仅能抑制肿瘤细胞增殖,且对TK活性有较强的抑制作用。Erlotinib能促进A549细胞ROS的生成,激活JNK信号转导,诱发线粒体途径的凋亡,该新机制的发现为将喹唑啉类化合物发展为更有效的抗肿瘤药物积累了必要的学术与实验基础。
Tumor therapy has been a worldwide problem. As our knowledge of signal transduction pathways in tumor cells increases, drug design against tumor-specific molecular targets attracts more and more attention. Furthermore, with the development of the crystal diffraction techniques, combinatorial chemistry, molecular model, high-throughput screening technology and computer chemistry, targeted agents change with each passing day, providing new stratigies for tumor therapy. Drug design based on the structure and mechanism has become the mainstream form of developing antitumor agents.
Epidermal growth factor receptor (EGFR), one member of the ErbB family, is an important transmembrane receptor with tyrosine kinase (TK) activity. EGFR signaling passway is associated with cell migration, adhesion, proliferation, differentiation as well as apoptosis. Therefore, it is closely related to tumor initiation and deterioration. EGFR gene was first cloned in 1984. Studies over the past two decades have shown that EGFR is a promising molecular target for tumor therapy. In recent years, analyses of the bioactivities of quinazoline compounds suggest that they are a class of micromolecular compounds with mutiple pharmacological activities, particularly inhibiting EGFR-TK activity. Erlotinib is a micromolecular EGFR-TK inhibitor (EGFR-TKI) jointly developed by Genentech, Roche and OSI companies, belonging to the quinazoline compounds. It competitively inhibits the binding of ATP with the intracellular catalytic sites of EGFR, thus reducing the autophosphorylation of EGFR and resulting in cell growth arrest and apoptosis. Another study found that Erlotinib could induce the expression of cyclin dependent kinase inhibitor p27~(KIP1) and suppress cell-cycle events involved in the G1/S transition.
Although people have obtained many milestone achievements of the EGFR-targeted antitumor agents, yet a number of problems remain to be solved: how to make such agents only act on the assumed target of tumor cells, but not the same target of normal cells; in the therapeutic alliance, how to make the choice of combined or synergistic effects. These unsolved problems hamper the clinlical application of EGFR-targeted antitumor agents. Therefore, researches conercering the mechanisms and applications of EGFR-targeted antitumor agents are of great importance.
In the present study, we first took in vitro screening for the antitumor activities of new quinazoline compounds and investigated their effects on TK activities. Then we explored the novel mechanism involved in the antitumor action of quinazoline compounds, taking erlotinib as a representative agent. The aim of this study is to provide candidate compounds for molecular target-based tumor therapy and accumulate the necessary academic and experimental bases for quinazoline compounds to become more efficient antitumor agents.
Part I : Screening for the antitumor activities of quinazoline compounds
AIMS: To screen for the antitumor activities of new quinazoline compounds and investigate their effects on TK activities.
METHODS: Tumor cell viability was measured by MTT method. ELISA kit was used to determine TK activity.
RESULTS: Compared with gefitinib or erlotinib group, the proliferation of tumor cells treated with GI-2～GI-6 compounds, GII-2～GII-5 compounds, GIV-2、6 compounds, BI-2～BI-8 compounds, BII-2、5、7、8 compounds was markedly inhibited. The inhibitory effects of BI-2～BI-8 compounds were stronger than those of gefitinib or erlotinib at the same concentration; the highest inhibition ratio was over 90%. The results of ELISA showed that GI-5、6 compounds, GII-4、5 compounds, BI-8 compound, BII-5、7 compounds significantly suppressed TK activity.
CONCULATIONS: Among the seven series, 44 kinds of new compounds, GI-2～GI-6 compounds, GII-2～GII-5 compounds, GIV-2、6 compounds, BI-2～BI-8 compounds, BII-2、5、7、8 compounds could markedly inhibit tumor cell proliferation, showing more effective biological antitumor activities in vitro. The inhibitory effects of BI-2～BI-8 compounds were stronger than those of gefitinib, erlotinib and other new compounds at the same concentration; GI-5、6 compounds, GII-4、5 compounds, BI-8 compound, BII-5、7 compounds significantly suppressed TK activity (P < 0.05). They were expected to become candidate compounds for tumor targeted therapy with a decent molecular target.
Part II Study on the novel mechanism involved in the antitumor action of erlotinib
AIMS: To investigate the novel mechanism involved in the antitumor action of erlotinib.
METHODS: Cell apoptosis was determined by staining with Hoechst 33324. Intracellular production of ROS was measured by the fluorescent probe DCFH-DA. Mitochondrial preparations from A549 cells were extracted and mitochondrial respiration function was determined by oxygen electrode. Superoxide ions (O_2~-) were detected by the fluorescent probe DHE. RT-PCR was taken for the measurement of NADPH oxidase catalytic subunit gp91~(phox). Cell viability was measured by MTT method. Mitochondrial membrane potential (ΔΨ_m) was assessed with the fluorescent probe JC-1. We introduced western blotting for the analyses of cytochrome C, apoptosis-inducing factor (AIF), c-Jun NH_2-terminal kinase (JNK), p-JNK.
RESULTS: 1) Erlotinib induced apoptosis in A549 cells concentration-dependently. 2) Erlotinib incubation for 30 min promoted ROS generation in A549 cells in a concentration-dependent manner. 3) Erlotinib increased RCR dose-dependently in A549 cells. Erlotinib (10μM) inhibited state 4 respiration. 4) Erlotinib incubation for 30 min concentration-dependently induced O_2~- production and increased the mRNA levels of NADPH oxidase catalytic subunit gp91 in A549 cells. 5) Pretreatment with NAC (1 mM) inhibited erlotinib (10μM)-induced cell death. 6) Erlotinib incubation for 24 h caused loss ofΔΨ_m and induced the release of cytochrome C and AIF from mitochondria in a dose-dependent manner. 7) Erlotinib incubation for 24 h induced JNK phosphorylation in A549 cells in a concentration-dependent manner.
CONCLUSIONS: Erlotinib exerts an antitumor activity by activating ROS-dependent, JNK mediated and mitochrondrial-initiated cell apoptosis.
This study showed that quinazoline compounds could be developed into new agents with better antitumor activities after optimized design. They could not only prevent tumor cell proliferation but also suppress TK activity. Our study also demonstrated that erlotinib could exert an antitumor effect via increasing ROS production, activating JNK, and thereby initiating mitochondrial death pathways. These findings accumulated the necessary academic and experimental bases for quinazoline compounds to become more efficient antitumor agents.
表皮生长因子受体(epidermal growth factor receptor,EGFR)是ErbB家族的成员之一,具有酪氨酸激酶(tyrosine kinase,TK)活性,是一种重要的跨膜受体。EGFR信号通路关乎细胞的迁移、黏附、增殖、分化、凋亡,与肿瘤的形成和恶化密切相关。从1984年EGFR基因首次被克隆,20多年来的研究显示,EGFR是肿瘤治疗中一个富有前景的靶分子。近年来对喹唑啉类化合物生物活性的分析可见,该类化合物是一类具有多重药理作用的小分子化合物,其对EGFR-TK活性的抑制作用尤为突出。埃罗替尼(Erlotinib)是Genentech公司、Roche公司和OSI公司联合开发的一种小分子EGFR-TK抑制剂(EGFR-TK inhibitor,EGFR-TKI),属喹唑啉类化合物。其主要作用机制为竞争性抑制三磷酸腺苷(adenosine-triphosphate,ATP)与EGFR胞内催化位点的结合,降低EGFR的自身磷酸化作用,从而导致细胞生长停滞并走向凋亡。另有研究发现,Erlotinib可诱导细胞周期抑制蛋白p27~(KIP1)的表达,使细胞周期阻滞于G1期。
虽然对靶向EGFR的抗肿瘤药物的研究已取得许多具有里程碑意义的成绩,但仍有很多问题亟待解决:如何使此类药物只作用于肿瘤细胞的拟定靶点,而不作用于正常细胞的相同靶点;在联合疗法中,如何进行疗效相加或协同的选择等。这些都阻碍了靶向EGFR的抗肿瘤药物的临床应用。因此,关于靶向EGFR的抗肿瘤药物的作用机制和适用范围等的研究具有深远的意义。
本文工作第一部分是在离体水平初步筛选系列喹唑啉类新化合物的抗肿瘤作用并研究其对TK活性的影响;第二部分以Erlotinib为代表,探讨喹唑啉类化合物抗肿瘤作用的新机制,旨在为肿瘤的分子靶向治疗提供新的候选化合物,并为将喹唑啉类化合物发展为更有效的抗肿瘤药物积累必要的学术与实验基础。
第一部分喹唑啉类化合物抗肿瘤活性的筛选
目的:筛选系列喹唑啉类新化合物的抗肿瘤作用并研究其对TK活性的影响。
方法:MTT法测定肿瘤细胞活力;酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)试剂盒测定TK活性。
结果:与Gefitinib、Erlotinib相比,GⅠ系列2～6号化合物,GⅡ系列2～5号化合物,GⅣ系列2、6号化合物,BⅠ系列2～8号化合物,BⅡ系列2、5、7、8号化合物明显抑制肿瘤细胞增殖,其中BⅠ系列2～8号化合物抑制效应明显强于同浓度阳性药物,最高抑制率超过90%。ELISA法测定21种初筛有效的新化合物对细胞TK活性的影响,结果显示,GⅠ系列5、6号化合物,GⅡ系列4、5号化合物,BⅠ系列8号化合物,BⅡ系列5、7号化合物可显著抑制TK活性。
结论:七个系列共计44种新化合物中,GⅠ系列2～6号化合物,GⅡ系列2～5号化合物,GⅣ系列2、6号化合物,BⅠ系列2～8号化合物,BⅡ系列2、5、7、8号化合物能够明显抑制肿瘤细胞株的增殖,体外显示良好的生物抑瘤作用,BⅠ系列2～8号化合物作用明显强于同浓度的Gefitinib、Erlotinib和其他新化合物;其中GⅠ系列5、6号化合物,GⅡ系列4、5号化合物,BⅠ系列8号化合物,BⅡ系列5、7号化合物对细胞TK活性的抑制效应显著(P＜0.05),具有良好的分子靶向性,有望成为肿瘤靶向治疗的候选化合物。
第二部分Erlotinib抗肿瘤新机制的研究
目的:探讨Erlotinib抗肿瘤效应的新机制。
方法:hoechst 33342荧光染色测定细胞凋亡;DCFH-DA荧光探针检测胞内活性氧簇(reactive oxygen species,ROS);提取A549细胞线粒体,氧电极法测定线粒体呼吸功能;DHE荧光探针检测胞内超氧化物阴离子(O_2~-);RT-PCR法测定NADPH氧化酶催化亚基gp91的表达变化;MTT法测定细胞活力;JC-1荧光探针检测线粒体膜电位(mitochondrial membrane potential,△Ψ_m);western-blotting法测定细胞色素C,凋亡诱导因子(apoptosis-inducing factor,AIF),c-Jun NH_2端激酶(c-Jun NH_2-terminal kinase,JNK),磷酸化JNK(p-JNK)的表达变化。
结果:1)Erlotinib呈浓度依赖性诱导A549细胞的凋亡。2)Erlotinib作用30 min呈浓度依赖性增加A549细胞胞内的ROS水平。3)Erlotinib呈浓度依赖性增加A549细胞的线粒体呼吸控制率(respiratory control ratio,RCR),Erlotinib(10μM)可降低Ⅳ态呼吸。4)Erlotinib作用30 min呈浓度依赖性促进A549细胞O_2~-的产生并增加A549细胞NADPH氧化酶催化亚基gp91的mRNA水平。5)抗氧化剂N-乙酰半胱氨酸(N-acetyl-L-cysteine,NAC)(1 mM)可抑制Erlotinib(10μM)降低细胞活力的作用。6)Erlotinib作用24 h呈浓度依赖性降低A549细胞的△Ψ_m,并促进A549细胞线粒体内细胞色素C和AIF的释放。7)Erlotinib作用24 h呈浓度依赖性促进A549细胞JNK的磷酸化。
结论:Erlotinib可通过增加ROS的产生,活化JNK,激活线粒体凋亡通路而发挥抗肿瘤作用。
本文研究工作表明喹唑啉类化合物经优化设计后,可形成活性较高的新化合物。它们不仅能抑制肿瘤细胞增殖,且对TK活性有较强的抑制作用。Erlotinib能促进A549细胞ROS的生成,激活JNK信号转导,诱发线粒体途径的凋亡,该新机制的发现为将喹唑啉类化合物发展为更有效的抗肿瘤药物积累了必要的学术与实验基础。
Tumor therapy has been a worldwide problem. As our knowledge of signal transduction pathways in tumor cells increases, drug design against tumor-specific molecular targets attracts more and more attention. Furthermore, with the development of the crystal diffraction techniques, combinatorial chemistry, molecular model, high-throughput screening technology and computer chemistry, targeted agents change with each passing day, providing new stratigies for tumor therapy. Drug design based on the structure and mechanism has become the mainstream form of developing antitumor agents.
Epidermal growth factor receptor (EGFR), one member of the ErbB family, is an important transmembrane receptor with tyrosine kinase (TK) activity. EGFR signaling passway is associated with cell migration, adhesion, proliferation, differentiation as well as apoptosis. Therefore, it is closely related to tumor initiation and deterioration. EGFR gene was first cloned in 1984. Studies over the past two decades have shown that EGFR is a promising molecular target for tumor therapy. In recent years, analyses of the bioactivities of quinazoline compounds suggest that they are a class of micromolecular compounds with mutiple pharmacological activities, particularly inhibiting EGFR-TK activity. Erlotinib is a micromolecular EGFR-TK inhibitor (EGFR-TKI) jointly developed by Genentech, Roche and OSI companies, belonging to the quinazoline compounds. It competitively inhibits the binding of ATP with the intracellular catalytic sites of EGFR, thus reducing the autophosphorylation of EGFR and resulting in cell growth arrest and apoptosis. Another study found that Erlotinib could induce the expression of cyclin dependent kinase inhibitor p27~(KIP1) and suppress cell-cycle events involved in the G1/S transition.
Although people have obtained many milestone achievements of the EGFR-targeted antitumor agents, yet a number of problems remain to be solved: how to make such agents only act on the assumed target of tumor cells, but not the same target of normal cells; in the therapeutic alliance, how to make the choice of combined or synergistic effects. These unsolved problems hamper the clinlical application of EGFR-targeted antitumor agents. Therefore, researches conercering the mechanisms and applications of EGFR-targeted antitumor agents are of great importance.
In the present study, we first took in vitro screening for the antitumor activities of new quinazoline compounds and investigated their effects on TK activities. Then we explored the novel mechanism involved in the antitumor action of quinazoline compounds, taking erlotinib as a representative agent. The aim of this study is to provide candidate compounds for molecular target-based tumor therapy and accumulate the necessary academic and experimental bases for quinazoline compounds to become more efficient antitumor agents.
Part I : Screening for the antitumor activities of quinazoline compounds
AIMS: To screen for the antitumor activities of new quinazoline compounds and investigate their effects on TK activities.
METHODS: Tumor cell viability was measured by MTT method. ELISA kit was used to determine TK activity.
RESULTS: Compared with gefitinib or erlotinib group, the proliferation of tumor cells treated with GI-2～GI-6 compounds, GII-2～GII-5 compounds, GIV-2、6 compounds, BI-2～BI-8 compounds, BII-2、5、7、8 compounds was markedly inhibited. The inhibitory effects of BI-2～BI-8 compounds were stronger than those of gefitinib or erlotinib at the same concentration; the highest inhibition ratio was over 90%. The results of ELISA showed that GI-5、6 compounds, GII-4、5 compounds, BI-8 compound, BII-5、7 compounds significantly suppressed TK activity.
CONCULATIONS: Among the seven series, 44 kinds of new compounds, GI-2～GI-6 compounds, GII-2～GII-5 compounds, GIV-2、6 compounds, BI-2～BI-8 compounds, BII-2、5、7、8 compounds could markedly inhibit tumor cell proliferation, showing more effective biological antitumor activities in vitro. The inhibitory effects of BI-2～BI-8 compounds were stronger than those of gefitinib, erlotinib and other new compounds at the same concentration; GI-5、6 compounds, GII-4、5 compounds, BI-8 compound, BII-5、7 compounds significantly suppressed TK activity (P < 0.05). They were expected to become candidate compounds for tumor targeted therapy with a decent molecular target.
Part II Study on the novel mechanism involved in the antitumor action of erlotinib
AIMS: To investigate the novel mechanism involved in the antitumor action of erlotinib.
METHODS: Cell apoptosis was determined by staining with Hoechst 33324. Intracellular production of ROS was measured by the fluorescent probe DCFH-DA. Mitochondrial preparations from A549 cells were extracted and mitochondrial respiration function was determined by oxygen electrode. Superoxide ions (O_2~-) were detected by the fluorescent probe DHE. RT-PCR was taken for the measurement of NADPH oxidase catalytic subunit gp91~(phox). Cell viability was measured by MTT method. Mitochondrial membrane potential (ΔΨ_m) was assessed with the fluorescent probe JC-1. We introduced western blotting for the analyses of cytochrome C, apoptosis-inducing factor (AIF), c-Jun NH_2-terminal kinase (JNK), p-JNK.
RESULTS: 1) Erlotinib induced apoptosis in A549 cells concentration-dependently. 2) Erlotinib incubation for 30 min promoted ROS generation in A549 cells in a concentration-dependent manner. 3) Erlotinib increased RCR dose-dependently in A549 cells. Erlotinib (10μM) inhibited state 4 respiration. 4) Erlotinib incubation for 30 min concentration-dependently induced O_2~- production and increased the mRNA levels of NADPH oxidase catalytic subunit gp91 in A549 cells. 5) Pretreatment with NAC (1 mM) inhibited erlotinib (10μM)-induced cell death. 6) Erlotinib incubation for 24 h caused loss ofΔΨ_m and induced the release of cytochrome C and AIF from mitochondria in a dose-dependent manner. 7) Erlotinib incubation for 24 h induced JNK phosphorylation in A549 cells in a concentration-dependent manner.
CONCLUSIONS: Erlotinib exerts an antitumor activity by activating ROS-dependent, JNK mediated and mitochrondrial-initiated cell apoptosis.
This study showed that quinazoline compounds could be developed into new agents with better antitumor activities after optimized design. They could not only prevent tumor cell proliferation but also suppress TK activity. Our study also demonstrated that erlotinib could exert an antitumor effect via increasing ROS production, activating JNK, and thereby initiating mitochondrial death pathways. These findings accumulated the necessary academic and experimental bases for quinazoline compounds to become more efficient antitumor agents.
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