Notch1信号蛋白在卵巢癌发生中的作用及其机制研究
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摘要
研究背景
卵巢癌是发生于卵巢组织的恶性肿瘤,占所有妇科恶性肿瘤的15%左右,仅次于宫颈癌,而死亡率却位居第一。卵巢癌由于起病隐匿、早期不易发现,75%卵巢癌患者确诊时已发生转移[1, 2]。因此,更好的了解卵巢癌发生发展的分子机制对其早期诊断、早期治疗有着重要意义。
Notch信号通路是一条高度保守的决定细胞命运的信号通路[3],其受体和配体是通过细胞间的相互作用调节细胞功能的I型跨膜蛋白[3, 4]。在哺乳动物中,Notch信号通路包括四个受体(Notch1-Notch4)和5个配体(Jagged-1, Jagged-2, Delta-like-1, Delta-like-3 and Delta-like-4 and)[5],相邻细胞受体及配体之间相互作用诱导γ分泌酶介导的蛋白水解酶的释放导致Notch胞内段(NICD)的断裂[6],活化的NICD可进入细胞核与转录抑制因子CBF1结合,最终导致Hes、Hey等靶基因的释放[7, 8],Notch信号通路及其下游目的基因在细胞增值、分化、凋亡过程中有着重要作用[3]。
异常表达的Notch信号蛋白与多种恶性肿瘤的发生有关[9, 10]。Notch1表现为癌基因或抑癌基因取决于细胞的类型,它在鼠类皮肤肿瘤及非小细胞性肺癌中表现为抑癌基因作用[11, 12];而在许多其他肿瘤,如肾癌、胰腺癌、乳腺癌、前列腺癌中表现为癌基因作用[13]。最新文献报道,Notch3及其目的基因Pbx1在卵巢癌中起癌基因作用[14, 15];Notch1在卵巢癌患者腹水中有表达,并有促癌作用[16, 17]。这些表明,Notch信号通路在卵巢癌的发生过程中可能起癌基因作用。Notch信号蛋白与卵巢癌的关系是一个新的研究领域,也为卵巢癌的基因治疗提供了新的思路。
目的
(1)探讨Notch1在卵巢癌形成和转化过程中的表达特点及其与卵巢癌的临床病理学参数的关系;
(2)检测卵巢癌细胞系A2780, SKOV3, HO-8910, HO-8910PM和卵巢上皮细胞IOSE 144中Notch1及下游基因hes1的表达,筛选Notch1信号蛋白高表达的细胞系,为进一步实验研究提供实验依据;
(3)检测γ-分泌酶抑制剂DAPT阻断Notch信号通路后Notch1及hes1基因的变化情况及对卵巢癌细胞A2780生长、凋亡等生物学行为的影响,为进一步实验研究提供实验依据;
(4)检测γ-分泌酶抑制剂DAPT下调Notch信号通路对卵巢癌铂类耐药的影响。
方法
(1)采用免疫组织化学SP染色法、逆转录聚合酶链反应(RT-PCR)及Western blotting检测109例卵巢癌(其中65例为单侧卵巢癌)、65例单侧卵巢癌患者健侧卵巢(配对对照)及48例正常卵巢组织(正常对照)中Notch1的表达,采用SPSS14.0软件的卡方检验统计方法进行分析。
(2)采用逆转录聚合酶链反应(RT-PCR)及Western blotting检测四株卵巢癌细胞(A2780, SKOV3, HO-8910, HO-8910PM)及一株卵巢上皮细胞(IOSE 144)中Notch1及其下游基因hes1的表达情况;采用MTT、流式细胞术、ELISA及克隆形成实验检测γ-分泌酶抑制剂DAPT下调Notch信号通路对卵巢癌细胞生物学行为的影响。
(3)采用逆转录聚合酶链反应(RT-PCR)及Western blotting检测γ-分泌酶抑制剂DAPT处理卵巢癌铂类耐药细胞A2780/CP70后Notch信号通路下游基因hes1的变化情况,采用MTT、流式细胞术、ELISA及克隆形成实验检测DAPT联合顺铂(Cis-DDP)对卵巢癌铂类耐药细胞A2780/CP70生物学行为的影响。结果
(1)Notch1在卵巢癌中的表达与卵巢癌的组织分化程度及FIGO分期相关(P﹤0.05),而与年龄、家族史、肿瘤位置、有无腹水、有无周围组织浸润、有无淋巴结转移、病理类型差异无显著性(P>0.05);
(2)Notch1及其下游hes1基因在卵巢癌细胞A2780中高表达;
(3)DAPT能抑制卵巢癌细胞A2780 Notch1及hes1的表达,并呈时间、剂量依赖性;
(4)DAPT下调Notch1表达可抑制A2780细胞生长并诱导细胞G1期阻滞;
(5)DAPT下调Notch1表达可诱导A2780细胞凋亡;
(6)DAPT能下调卵巢癌铂类耐药细胞A2780/CP70 Notch信号通路下游hes1基因的表达;
(7)DAPT能促进Cis-DDP诱导细胞生长抑制;
(8)DAPT联合Cis-DDP用药能诱导卵巢癌铂类耐药细胞A2780/CP70细胞G2期阻滞;
(9)DAPT能促进Cis-DDP诱导卵巢癌铂类耐药细胞A2780/CP70凋亡。
结论
(1)Notch1在卵巢癌组织中的表达与卵巢癌组织分化程度及FIGO分期相关,临床分期越高、分化程度越低,Notch1的表达越低;反之,Notch1的表达越高,可能与其恶性程度有关。
(2)Notch1及其下游hes1基因在多种卵巢癌细胞系中均有表达,且在A2780细胞系中表达较高,可选A2780细胞作为靶细胞进行更深入的研究。
(3)DAPT可下调A2780细胞Notch1及其下游hes1的表达,并呈现时间和剂量依赖性;同时可引起A2780细胞生长抑制、细胞克隆数减少,并引起细胞G1期阻滞;还能引起A2780细胞凋亡,并呈时间依赖性,γ-分泌酶抑制剂DAPT可能成为卵巢癌治疗的一个新靶点。
(4)DAPT阻断Notch信号通路可增强卵巢癌铂类耐药细胞A2780/CP70对Cis-DDP的敏感性,协同低剂量Cis-DDP诱导A2780/CP70细胞生长抑制及凋亡,DAPT-顺铂联合用药可能成为卵巢癌治疗的一个新靶点。
本实验结果显示, Notch1及其下游hes1基因在卵巢癌组织及细胞系中均有表达,提示Notch信号通路可能是卵巢癌发生、发展的机制之一;γ-分泌酶抑制剂DAPT下调Notch信号通路可抑制卵巢癌A2780细胞生长、诱导细胞凋亡,与Cis-DDP联合用药可协同低剂量Cis-DDP诱导卵巢癌铂类耐药细胞A2780/CP70生长抑制及凋亡。因此,为卵巢癌的基因治疗提供了新的思路。
Background Ovarian cancer is the second most common gynecologic cancer among women and the first leading cause of death from gynecologic malignancy worldwide. Metastasis beyond the ovary is found in 75% of patients at the time of diagnosis due to the absence of symptoms in early stages and lack of a reliable method for early detection, resulting in a high mortality rate despite optimal surgery and aggressive chemotherapy [1, 2]. This necessitates a better understanding of the molecular events of ovarian cancer progression, which may play an important role in early diagnosis and early therapy.
Notch signaling is an evolutionarily conserved pathway that regulates critical cell fate decisions[3]. Notch ligands and receptors are type I membrane proteins that regulate cell fate during cell-cell contact [3, 4]. In mammals, the Notch family consists of four receptors (Notch1-Notch4) and five ligands (Jagged-1, Jagged-2, Delta-like-1, Delta-like-3 and Delta-like-4) [5]. Receptor–ligand interaction between two neighboring cells leads toγ-secretase–mediated proteolytic release of the Notch intracellular domain (NICD [6]. NICD then translocates into the nucleus, in which it interacts with the transcriptional cofactor CBF1 and transactivates gene targets such as those in the Hes and Hey families [7, 8]. Notch signaling and its gene targets control variety of processes, involving cell fate specification, differentiation, proliferation, and survival [3].
Abnormal Notch signaling has been documented in many cancers and has been associated with tumorigenesis[9, 10]. Notch1 can function as a tumor oncogene or a suppressor, depending on the cell type and context. For instance, it acts as a tumor suppressor in murine skin tumors and non-small cell lung cancer[11, 12], but it acts as a tumor oncogene in many other types of cancers, such as renal cancer, pancreatic cancer, breast cancer and prostate carcinomas[13]. Some reports show that Notch3 and its target gene Pbx1 may play an important role in the development of ovarian cancer[14, 15]. Notch1 is considered as a tumor oncogene in ovarian cancer and a higher Notchl protein expression is found in ovarian carcinoma cell lines[16, 17]. These reports hint that Notch signaling might play important roles in ovarian cancer. The relationship between Notch siganling and ovarial carcinoma is a new field of study,and it also may be a new gene therapy for ovarial carcinoma.
Purpose
(1) To study the significance of Notch1 expression in ovarial carcinoma transformation and progression and its relationship with clinical pathology characteristics.
(2)To determine the expression of Notch1 and hes1 in ovarian carcinoma cell lines and to screen target cells for further study at Notch1 in ovarian carcinomas. (3)To determine the expression of Notch1 and hes1 in A2780 cells after the inhibition of Notch signaling byγ-secretase inhibitor(DAPT) and study the biologic behavior of A2780 cells for providing experiment data for further study. (4) To determine the influence of cisplatin resistance by down-regulation of Notch signaling byγ-secretase inhibitor(DAPT).
Methods
(1) using Immunohistochemistry, real-time polymerase chain reaction and Western Blot examine the expression of Notch1 in 109 ovarian cancer tissues, 65 patient-matched opposite side normal ovarian tissues and 48 normal ovarian tissues. They are analyzed by Chi-square test of SPSS14.0.
(2)using real-time polymerase chain reaction and Western Blot examine the expressions of Notch1 and hes1 in ovarian carcinoma cell lines A2780, SKOV3, HO-8910, HO-8910PM and IOSE 144 and using MTT assay, Flow cytometry, ELISA, colony-forming assay to examine biologic behavior of ovarian cancer cells after the inhibition of Notch signaling byγ-secretase inhibitor(DAPT).
(3) using real-time polymerase chain reaction and Western Blot examine the expressions of hes1 after the treatment of DAPT on ovarian cancer cisplatin-resistant cells A2780/CP70 and using MTT assay, Flow cytometry, ELISA, colony-forming assay to examine biologic behavior of A2780/CP70 after DAPT-cisplatin combination on A2780/CP70 cells.
Results:
(1)The expression of Notch1 in ovarian cancers was correlated with differentiation status and FIGO stage(P﹤0.05), not with age, family history, tumor location, ascites, adjacent tissue infiltration, lymphaden metachoresis and pathology subtypes(P>0.05).
(2) Notch1 and hes1 are highly expressed in ovarian cancer cells A2780.
(3) DAPT could down-regulate the expression of Notch1 and hes1 in a time-dependent and dose-dependent manner.
(4) Down-regulation of Notch1 expression by DAPT inhibited A2780 cell growth and induced cell cycle G1 arrest.
(5) Down-regulation of Notch1 expression by DAPT induced apoptosis in A2780 cells.
(6) Notch signaling and its target gene hes1 are downregulated by DAPT in A2780/CP70 cells.
(7) DAPT potentiates cisplatin-induced growth inhibition in a drug sequence–dependent manner.
(8) DAPT-cisplatin combination arrests cisplatin-resistant A2780/CP70 cells in G2 phase.
(9) DAPT enhances cisplatin-induced apoptosis in A2780/CP70 cells.
Conclusion:
(1) Notch1 expression was increased with decreasing levels of differentiation, as well as with increasing FIGO stage, that means the higher malignancy of the tumor is relevant to the higher Notch1 expression levels.
(2) Notch1 and hes1 are expressed in lots of ovarian cancer cell lines and highly expressed in ovarian cancer cells A2780. So, we could choose A2780 to finish the subsequent studies.
(3) DAPT could down-regulate the expression of Notch1 and hes1 in a time-dependent and dose-dependent manner and also inhibited A2780 cell growth and induced cell cycle G1 arrest and induced A2780 cells apoptosis.γ-secretase inhibitor(DAPT) may be a potential target of new therapeutic investigation in ovarian cancer.
(4) DAPT could sensitize the cisplatin-resistant ovarian cancer A2780/CP70 cells to cisplatin induced cytotoxicity and potentiates cisplatin-induced growth inhibition and also enhances cisplatin-induced apoptosis in A2780/CP70 cells. DAPT-cisplatin combination may be a target for the development of novel therapies for ovarian cancer.
卵巢癌是发生于卵巢组织的恶性肿瘤,占所有妇科恶性肿瘤的15%左右,仅次于宫颈癌,而死亡率却位居第一。卵巢癌由于起病隐匿、早期不易发现,75%卵巢癌患者确诊时已发生转移[1, 2]。因此,更好的了解卵巢癌发生发展的分子机制对其早期诊断、早期治疗有着重要意义。
Notch信号通路是一条高度保守的决定细胞命运的信号通路[3],其受体和配体是通过细胞间的相互作用调节细胞功能的I型跨膜蛋白[3, 4]。在哺乳动物中,Notch信号通路包括四个受体(Notch1-Notch4)和5个配体(Jagged-1, Jagged-2, Delta-like-1, Delta-like-3 and Delta-like-4 and)[5],相邻细胞受体及配体之间相互作用诱导γ分泌酶介导的蛋白水解酶的释放导致Notch胞内段(NICD)的断裂[6],活化的NICD可进入细胞核与转录抑制因子CBF1结合,最终导致Hes、Hey等靶基因的释放[7, 8],Notch信号通路及其下游目的基因在细胞增值、分化、凋亡过程中有着重要作用[3]。
异常表达的Notch信号蛋白与多种恶性肿瘤的发生有关[9, 10]。Notch1表现为癌基因或抑癌基因取决于细胞的类型,它在鼠类皮肤肿瘤及非小细胞性肺癌中表现为抑癌基因作用[11, 12];而在许多其他肿瘤,如肾癌、胰腺癌、乳腺癌、前列腺癌中表现为癌基因作用[13]。最新文献报道,Notch3及其目的基因Pbx1在卵巢癌中起癌基因作用[14, 15];Notch1在卵巢癌患者腹水中有表达,并有促癌作用[16, 17]。这些表明,Notch信号通路在卵巢癌的发生过程中可能起癌基因作用。Notch信号蛋白与卵巢癌的关系是一个新的研究领域,也为卵巢癌的基因治疗提供了新的思路。
目的
(1)探讨Notch1在卵巢癌形成和转化过程中的表达特点及其与卵巢癌的临床病理学参数的关系;
(2)检测卵巢癌细胞系A2780, SKOV3, HO-8910, HO-8910PM和卵巢上皮细胞IOSE 144中Notch1及下游基因hes1的表达,筛选Notch1信号蛋白高表达的细胞系,为进一步实验研究提供实验依据;
(3)检测γ-分泌酶抑制剂DAPT阻断Notch信号通路后Notch1及hes1基因的变化情况及对卵巢癌细胞A2780生长、凋亡等生物学行为的影响,为进一步实验研究提供实验依据;
(4)检测γ-分泌酶抑制剂DAPT下调Notch信号通路对卵巢癌铂类耐药的影响。
方法
(1)采用免疫组织化学SP染色法、逆转录聚合酶链反应(RT-PCR)及Western blotting检测109例卵巢癌(其中65例为单侧卵巢癌)、65例单侧卵巢癌患者健侧卵巢(配对对照)及48例正常卵巢组织(正常对照)中Notch1的表达,采用SPSS14.0软件的卡方检验统计方法进行分析。
(2)采用逆转录聚合酶链反应(RT-PCR)及Western blotting检测四株卵巢癌细胞(A2780, SKOV3, HO-8910, HO-8910PM)及一株卵巢上皮细胞(IOSE 144)中Notch1及其下游基因hes1的表达情况;采用MTT、流式细胞术、ELISA及克隆形成实验检测γ-分泌酶抑制剂DAPT下调Notch信号通路对卵巢癌细胞生物学行为的影响。
(3)采用逆转录聚合酶链反应(RT-PCR)及Western blotting检测γ-分泌酶抑制剂DAPT处理卵巢癌铂类耐药细胞A2780/CP70后Notch信号通路下游基因hes1的变化情况,采用MTT、流式细胞术、ELISA及克隆形成实验检测DAPT联合顺铂(Cis-DDP)对卵巢癌铂类耐药细胞A2780/CP70生物学行为的影响。结果
(1)Notch1在卵巢癌中的表达与卵巢癌的组织分化程度及FIGO分期相关(P﹤0.05),而与年龄、家族史、肿瘤位置、有无腹水、有无周围组织浸润、有无淋巴结转移、病理类型差异无显著性(P>0.05);
(2)Notch1及其下游hes1基因在卵巢癌细胞A2780中高表达;
(3)DAPT能抑制卵巢癌细胞A2780 Notch1及hes1的表达,并呈时间、剂量依赖性;
(4)DAPT下调Notch1表达可抑制A2780细胞生长并诱导细胞G1期阻滞;
(5)DAPT下调Notch1表达可诱导A2780细胞凋亡;
(6)DAPT能下调卵巢癌铂类耐药细胞A2780/CP70 Notch信号通路下游hes1基因的表达;
(7)DAPT能促进Cis-DDP诱导细胞生长抑制;
(8)DAPT联合Cis-DDP用药能诱导卵巢癌铂类耐药细胞A2780/CP70细胞G2期阻滞;
(9)DAPT能促进Cis-DDP诱导卵巢癌铂类耐药细胞A2780/CP70凋亡。
结论
(1)Notch1在卵巢癌组织中的表达与卵巢癌组织分化程度及FIGO分期相关,临床分期越高、分化程度越低,Notch1的表达越低;反之,Notch1的表达越高,可能与其恶性程度有关。
(2)Notch1及其下游hes1基因在多种卵巢癌细胞系中均有表达,且在A2780细胞系中表达较高,可选A2780细胞作为靶细胞进行更深入的研究。
(3)DAPT可下调A2780细胞Notch1及其下游hes1的表达,并呈现时间和剂量依赖性;同时可引起A2780细胞生长抑制、细胞克隆数减少,并引起细胞G1期阻滞;还能引起A2780细胞凋亡,并呈时间依赖性,γ-分泌酶抑制剂DAPT可能成为卵巢癌治疗的一个新靶点。
(4)DAPT阻断Notch信号通路可增强卵巢癌铂类耐药细胞A2780/CP70对Cis-DDP的敏感性,协同低剂量Cis-DDP诱导A2780/CP70细胞生长抑制及凋亡,DAPT-顺铂联合用药可能成为卵巢癌治疗的一个新靶点。
本实验结果显示, Notch1及其下游hes1基因在卵巢癌组织及细胞系中均有表达,提示Notch信号通路可能是卵巢癌发生、发展的机制之一;γ-分泌酶抑制剂DAPT下调Notch信号通路可抑制卵巢癌A2780细胞生长、诱导细胞凋亡,与Cis-DDP联合用药可协同低剂量Cis-DDP诱导卵巢癌铂类耐药细胞A2780/CP70生长抑制及凋亡。因此,为卵巢癌的基因治疗提供了新的思路。
Background Ovarian cancer is the second most common gynecologic cancer among women and the first leading cause of death from gynecologic malignancy worldwide. Metastasis beyond the ovary is found in 75% of patients at the time of diagnosis due to the absence of symptoms in early stages and lack of a reliable method for early detection, resulting in a high mortality rate despite optimal surgery and aggressive chemotherapy [1, 2]. This necessitates a better understanding of the molecular events of ovarian cancer progression, which may play an important role in early diagnosis and early therapy.
Notch signaling is an evolutionarily conserved pathway that regulates critical cell fate decisions[3]. Notch ligands and receptors are type I membrane proteins that regulate cell fate during cell-cell contact [3, 4]. In mammals, the Notch family consists of four receptors (Notch1-Notch4) and five ligands (Jagged-1, Jagged-2, Delta-like-1, Delta-like-3 and Delta-like-4) [5]. Receptor–ligand interaction between two neighboring cells leads toγ-secretase–mediated proteolytic release of the Notch intracellular domain (NICD [6]. NICD then translocates into the nucleus, in which it interacts with the transcriptional cofactor CBF1 and transactivates gene targets such as those in the Hes and Hey families [7, 8]. Notch signaling and its gene targets control variety of processes, involving cell fate specification, differentiation, proliferation, and survival [3].
Abnormal Notch signaling has been documented in many cancers and has been associated with tumorigenesis[9, 10]. Notch1 can function as a tumor oncogene or a suppressor, depending on the cell type and context. For instance, it acts as a tumor suppressor in murine skin tumors and non-small cell lung cancer[11, 12], but it acts as a tumor oncogene in many other types of cancers, such as renal cancer, pancreatic cancer, breast cancer and prostate carcinomas[13]. Some reports show that Notch3 and its target gene Pbx1 may play an important role in the development of ovarian cancer[14, 15]. Notch1 is considered as a tumor oncogene in ovarian cancer and a higher Notchl protein expression is found in ovarian carcinoma cell lines[16, 17]. These reports hint that Notch signaling might play important roles in ovarian cancer. The relationship between Notch siganling and ovarial carcinoma is a new field of study,and it also may be a new gene therapy for ovarial carcinoma.
Purpose
(1) To study the significance of Notch1 expression in ovarial carcinoma transformation and progression and its relationship with clinical pathology characteristics.
(2)To determine the expression of Notch1 and hes1 in ovarian carcinoma cell lines and to screen target cells for further study at Notch1 in ovarian carcinomas. (3)To determine the expression of Notch1 and hes1 in A2780 cells after the inhibition of Notch signaling byγ-secretase inhibitor(DAPT) and study the biologic behavior of A2780 cells for providing experiment data for further study. (4) To determine the influence of cisplatin resistance by down-regulation of Notch signaling byγ-secretase inhibitor(DAPT).
Methods
(1) using Immunohistochemistry, real-time polymerase chain reaction and Western Blot examine the expression of Notch1 in 109 ovarian cancer tissues, 65 patient-matched opposite side normal ovarian tissues and 48 normal ovarian tissues. They are analyzed by Chi-square test of SPSS14.0.
(2)using real-time polymerase chain reaction and Western Blot examine the expressions of Notch1 and hes1 in ovarian carcinoma cell lines A2780, SKOV3, HO-8910, HO-8910PM and IOSE 144 and using MTT assay, Flow cytometry, ELISA, colony-forming assay to examine biologic behavior of ovarian cancer cells after the inhibition of Notch signaling byγ-secretase inhibitor(DAPT).
(3) using real-time polymerase chain reaction and Western Blot examine the expressions of hes1 after the treatment of DAPT on ovarian cancer cisplatin-resistant cells A2780/CP70 and using MTT assay, Flow cytometry, ELISA, colony-forming assay to examine biologic behavior of A2780/CP70 after DAPT-cisplatin combination on A2780/CP70 cells.
Results:
(1)The expression of Notch1 in ovarian cancers was correlated with differentiation status and FIGO stage(P﹤0.05), not with age, family history, tumor location, ascites, adjacent tissue infiltration, lymphaden metachoresis and pathology subtypes(P>0.05).
(2) Notch1 and hes1 are highly expressed in ovarian cancer cells A2780.
(3) DAPT could down-regulate the expression of Notch1 and hes1 in a time-dependent and dose-dependent manner.
(4) Down-regulation of Notch1 expression by DAPT inhibited A2780 cell growth and induced cell cycle G1 arrest.
(5) Down-regulation of Notch1 expression by DAPT induced apoptosis in A2780 cells.
(6) Notch signaling and its target gene hes1 are downregulated by DAPT in A2780/CP70 cells.
(7) DAPT potentiates cisplatin-induced growth inhibition in a drug sequence–dependent manner.
(8) DAPT-cisplatin combination arrests cisplatin-resistant A2780/CP70 cells in G2 phase.
(9) DAPT enhances cisplatin-induced apoptosis in A2780/CP70 cells.
Conclusion:
(1) Notch1 expression was increased with decreasing levels of differentiation, as well as with increasing FIGO stage, that means the higher malignancy of the tumor is relevant to the higher Notch1 expression levels.
(2) Notch1 and hes1 are expressed in lots of ovarian cancer cell lines and highly expressed in ovarian cancer cells A2780. So, we could choose A2780 to finish the subsequent studies.
(3) DAPT could down-regulate the expression of Notch1 and hes1 in a time-dependent and dose-dependent manner and also inhibited A2780 cell growth and induced cell cycle G1 arrest and induced A2780 cells apoptosis.γ-secretase inhibitor(DAPT) may be a potential target of new therapeutic investigation in ovarian cancer.
(4) DAPT could sensitize the cisplatin-resistant ovarian cancer A2780/CP70 cells to cisplatin induced cytotoxicity and potentiates cisplatin-induced growth inhibition and also enhances cisplatin-induced apoptosis in A2780/CP70 cells. DAPT-cisplatin combination may be a target for the development of novel therapies for ovarian cancer.
引文
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