药学学报

Cancer type	Type of statins	Cell line	Mechanism
Colorectal cancer	All statins except pravastatin	DLD1/HT29/SW620/HCT116	EZH2
Lung cancer	Simvastatin/atorvastatin/lovastatin	A549	HDACs
Simvastatin	A549	MetT13/EZH2
Hepatocarcinoma	Simvastatin	HepG2	miR-192
Pancreatic cancer	Simvastatin	MiaPaCa2	HDAC1/5
Prostatic cancer	Simvastatin	PC3	HDACs
Renal carcinoma	Atorvastatin	-	HDACs
Glioma	Fluvastatin	GBM-8401	H2AX/H3/H4

Cancer type	Type of statins	Cell line	Mechanism
Colorectal cancer	All statins except pravastatin	DLD1/HT29/SW620/HCT116	EZH2
Lung cancer	Simvastatin/atorvastatin/lovastatin	A549	HDACs
Simvastatin	A549	MetT13/EZH2
Hepatocarcinoma	Simvastatin	HepG2	miR-192
Pancreatic cancer	Simvastatin	MiaPaCa2	HDAC1/5
Prostatic cancer	Simvastatin	PC3	HDACs
Renal carcinoma	Atorvastatin	-	HDACs
Glioma	Fluvastatin	GBM-8401	H2AX/H3/H4

Statin type	Cancer type	Research type	Number of patients	Dosage	Result	Ref
Atorvastatin	Non-Hodgkin lymphoma	Clinical trial	27	40 mg·d^-1, 6 months	The vascular endothelial function improved after treatment	[54]
	Prostatic cancer	Randomized control	160	80 mg·d^-1, 3-5 weeks	Inducing the decrease of adrenal androgen in men with prostate cancer	[55]
	Prostatic cancer	Clinical trial	364	20 mg·d^-1, 1 year	There was no significant difference in testosterone and sex hormone binding globulin levels between groups	[56]
	Squamous cell carcinoma of head and neck	Clinical trial	32	10-80 mg·d^-1, 4 weeks	Atorvastatin use was significantly associated with cisplatin-induced hearing loss reduction	[57]
Fluvastatin	Breast cancer	Clinical trial	35	20, 80 mg·d^-1, 6 weeks	Reduce tumor proliferation and increase apoptosis activity in high-grade breast cancer	[58]
Pravastatin	Hepatocarcinoma	Randomized control	91	40 mg·d^-1, 2 months	The median survival time of pravastatin group was 18 months, while that of control group was 9 months	[59]
Simvastatin	Intestinal cancer	Randomized control	132	40 mg·d^-1, 3 weeks	The plasma concentrations of IL-6, IL-8 and TNFα and the peritoneal concentrations of IL-6 and IL-8 decreased significantly after operation	[60]
	Multiple myeloma	Phase Ⅱ clinic	30	80 mg·d^-1, consistent with the course of chemotherapy	HMG-CoA/GG-PP/Rho/Rho kinase pathway mediates CAM-DR, and statins target this pathway to improve the efficacy of anti-myeloma treatment	[61]
	Breast cancer	Randomized control	150	20 mg·d^-1, 1 year	Compared with the placebo group, there was no obvious adverse reaction	[62]
	Breast cancer	Phase Ⅱ clinic	50	40 mg·d^-1, 6-7 months	The concentration of estrone sulfate decreased after simva-statin treatment, especially in postmenopausal subjects	[63]
	Lymphatic leiomyoma	Clinical trial	10	20-40 mg·d^-1, 4 months	Effects of simvastatin on growth inhibition and apoptosis promotion of TSC2-null cells	[64]

Statin type	Cancer type	Research type	Number of patients	Dosage	Result	Ref
Atorvastatin	Non-Hodgkin lymphoma	Clinical trial	27	40 mg·d^-1, 6 months	The vascular endothelial function improved after treatment	[54]
	Prostatic cancer	Randomized control	160	80 mg·d^-1, 3-5 weeks	Inducing the decrease of adrenal androgen in men with prostate cancer	[55]
	Prostatic cancer	Clinical trial	364	20 mg·d^-1, 1 year	There was no significant difference in testosterone and sex hormone binding globulin levels between groups	[56]
	Squamous cell carcinoma of head and neck	Clinical trial	32	10-80 mg·d^-1, 4 weeks	Atorvastatin use was significantly associated with cisplatin-induced hearing loss reduction	[57]
Fluvastatin	Breast cancer	Clinical trial	35	20, 80 mg·d^-1, 6 weeks	Reduce tumor proliferation and increase apoptosis activity in high-grade breast cancer	[58]
Pravastatin	Hepatocarcinoma	Randomized control	91	40 mg·d^-1, 2 months	The median survival time of pravastatin group was 18 months, while that of control group was 9 months	[59]
Simvastatin	Intestinal cancer	Randomized control	132	40 mg·d^-1, 3 weeks	The plasma concentrations of IL-6, IL-8 and TNFα and the peritoneal concentrations of IL-6 and IL-8 decreased significantly after operation	[60]
	Multiple myeloma	Phase Ⅱ clinic	30	80 mg·d^-1, consistent with the course of chemotherapy	HMG-CoA/GG-PP/Rho/Rho kinase pathway mediates CAM-DR, and statins target this pathway to improve the efficacy of anti-myeloma treatment	[61]
	Breast cancer	Randomized control	150	20 mg·d^-1, 1 year	Compared with the placebo group, there was no obvious adverse reaction	[62]
	Breast cancer	Phase Ⅱ clinic	50	40 mg·d^-1, 6-7 months	The concentration of estrone sulfate decreased after simva-statin treatment, especially in postmenopausal subjects	[63]
	Lymphatic leiomyoma	Clinical trial	10	20-40 mg·d^-1, 4 months	Effects of simvastatin on growth inhibition and apoptosis promotion of TSC2-null cells	[64]

Statin type	Cancer type	Clinical trial number	Progress	Number of participants	Dosage	Time
Atorvastatin	Prostatic cancer	NCT03819101	Ⅲ	1 210	80 mg·d^-1	2019.6.6
	Prostatic cancer	NCT04026230	Ⅲ	400	80 mg·d^-1	2019.8.15
	Prostatic cancer	NCT03830164	Ⅱ	270	Once a day for six weeks, and three times a day for one year after no obvious abnormality	2019.11.20
	Breast cancer	NCT03872388	Ⅱ	80	20, 80 mg·d^-1	2019.1.14
	Breast cancer	NCT04601116	Ⅲ	3 360	80 mg·d^-1, 2 years	2021.1.4
	Breast cancer	NCT05103644	Ⅱ	60	80 mg·d^-1	2021.10.30
	Hemangioma	NCT02603328	Ⅰ+Ⅱ	80	80 mg·d^-1	2018.7.17
Pravastatin	Breast cancer	NCT04385433	Ⅲ	400	40 mg·d^-1, 1 year	2020.12.4
Rosuvastatin	Breast cancer	NCT05338723	Ⅲ	50	20 mg·d^-1, 6 months	2020.9.15
Simvastatin	Ovarian cancer	NCT04457089	Ⅰ	20	40 mg·d^-1, 6 months	2021.1.25
	Breast cancer	NCT03454529	Ⅱ	24	40 mg·d^-1, 2-4 weeks	2018.3.9
	Breast cancer	NCT03971019	Ⅲ	314	20 mg·d^-1	2019.3.28
	Breast cancer	NCT05550415	Ⅱ	26	40 mg·d^-1, 21 days	2022.8.19
	Pancreatic cancer	NCT03889795	Ⅰ	15	5, 20, 40 mg·d^-1	2019.6.5
	Hysteromyoma	NCT03400826	Ⅱ	60	40 mg·d^-1, 12 weeks	2018.8.20

Statin type	Cancer type	Clinical trial number	Progress	Number of participants	Dosage	Time
Atorvastatin	Prostatic cancer	NCT03819101	Ⅲ	1 210	80 mg·d^-1	2019.6.6
	Prostatic cancer	NCT04026230	Ⅲ	400	80 mg·d^-1	2019.8.15
	Prostatic cancer	NCT03830164	Ⅱ	270	Once a day for six weeks, and three times a day for one year after no obvious abnormality	2019.11.20
	Breast cancer	NCT03872388	Ⅱ	80	20, 80 mg·d^-1	2019.1.14
	Breast cancer	NCT04601116	Ⅲ	3 360	80 mg·d^-1, 2 years	2021.1.4
	Breast cancer	NCT05103644	Ⅱ	60	80 mg·d^-1	2021.10.30
	Hemangioma	NCT02603328	Ⅰ+Ⅱ	80	80 mg·d^-1	2018.7.17
Pravastatin	Breast cancer	NCT04385433	Ⅲ	400	40 mg·d^-1, 1 year	2020.12.4
Rosuvastatin	Breast cancer	NCT05338723	Ⅲ	50	20 mg·d^-1, 6 months	2020.9.15
Simvastatin	Ovarian cancer	NCT04457089	Ⅰ	20	40 mg·d^-1, 6 months	2021.1.25
	Breast cancer	NCT03454529	Ⅱ	24	40 mg·d^-1, 2-4 weeks	2018.3.9
	Breast cancer	NCT03971019	Ⅲ	314	20 mg·d^-1	2019.3.28
	Breast cancer	NCT05550415	Ⅱ	26	40 mg·d^-1, 21 days	2022.8.19
	Pancreatic cancer	NCT03889795	Ⅰ	15	5, 20, 40 mg·d^-1	2019.6.5
	Hysteromyoma	NCT03400826	Ⅱ	60	40 mg·d^-1, 12 weeks	2018.8.20

他汀类药物抗肿瘤作用的表观与非表观遗传调节及临床研究进展

PDF下载

王媛茹 ¹ , 李学军 ²^,^*

药学学报 | 综述 2023,58(8): 2146-2154

收起

药学学报 |综述 2023 , 58 (8) : 2146 -2154

他汀类药物抗肿瘤作用的表观与非表观遗传调节及临床研究进展

全屏

[Author(id=1198960102066713545, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960102213514197, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, authorId=1198960102066713545, language=EN, stringName=Yuan-ru WANG, firstName=Yuan-ru, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=¹, address=1. School of Pharmacy, Shihezi University, Shihezi 832000, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960102507115493, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, authorId=1198960102066713545, language=CN, stringName=王媛茹, firstName=媛茹, middleName=null, lastName=王, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=¹, address=1.石河子大学药学院, 新疆石河子 832000, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960101634700189, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, xref=null, ext=[AuthorCompanyExt(id=1198960101659866018, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, companyId=1198960101634700189, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. School of Pharmacy, Shihezi University, Shihezi 832000, China), AuthorCompanyExt(id=1198960101672448933, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, companyId=1198960101634700189, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.石河子大学药学院, 新疆石河子 832000)])]), Author(id=1198960102679081970, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=xjli@bjmu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1198960102838464514, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, authorId=1198960102679081970, language=EN, stringName=Xue-jun LI, firstName=Xue-jun, middleName=null, lastName=LI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=²^,^*, address=2. School of Basic Medical Science, Peking University, Beijing 100191, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960102976876559, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, authorId=1198960102679081970, language=CN, stringName=李学军, firstName=学军, middleName=null, lastName=李, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=²^,^*, address=2.北京大学医学部基础医学院, 北京 100191, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960101827638192, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, xref=null, ext=[AuthorCompanyExt(id=1198960101840221106, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, companyId=1198960101827638192, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. School of Basic Medical Science, Peking University, Beijing 100191, China), AuthorCompanyExt(id=1198960101852804019, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612846387469, companyId=1198960101827638192, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.北京大学医学部基础医学院, 北京 100191)])])]

王媛茹¹, 李学军²^,^*

作者信息

1.石河子大学药学院, 新疆石河子 832000

2.北京大学医学部基础医学院, 北京 100191

通讯作者:

*李学军, Tel: 86-10-82801421, E-mail: xjli@bjmu.edu.cn

The epigenetic and non-epigenetic regulation of statins on its anti-tumor effect and its clinical research progress

Yuan-ru WANG¹, Xue-jun LI²^,^*

Affiliations

1. School of Pharmacy, Shihezi University, Shihezi 832000, China

2. School of Basic Medical Science, Peking University, Beijing 100191, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0660

文章导航

摘要

收起

他汀类药物是一类羟甲基戊二酰辅酶A还原酶(hydroxymethylglutaryl coenzyme A, HMG-CoA) 抑制剂, 是目前临床广泛应用的降血脂药物, 对心血管系统疾病的防治尤为重要。近年来, 国内外多项研究认为他汀类药物在肿瘤防治中有独特的作用, 并得到广泛关注。在表观遗传调节机制方面, 他汀类药物主要通过DNA甲基化、组蛋白修饰和非编码RNA的调节影响肿瘤的进程。此外, 他汀类药物也能通过促进肿瘤细胞自噬、调节肿瘤细胞周期、促进肿瘤细胞凋亡等信号通路实现其抗肿瘤作用。因此, 对他汀类药物的研究为发现新型抗肿瘤治疗方式提供思路。本文就他汀类药物在防治常见肿瘤方面的作用进行综述, 包括其通过表观遗传调节抑制肿瘤发生发展的作用机制以及其他相关机制, 及其抗肿瘤的临床研究现状。

关键词

他汀类药物 / 肿瘤 / 表观遗传 / 临床研究 / 甲羟戊酸途径

Abstract

收起

Statins are a class of hydroxymethylglutaryl-CoA reductase inhibitors (HMG-CoA reductase inhibitors), which are widely used to reduce blood lipid in clinic, and are especially important for the prevention and treatment of cardiovascular diseases. In recent years, many studies at home and abroad believe that statins have a unique role in tumor prevention and treatment, and have been widely concerned. In terms of epigenetic regulation mechanism, statins mainly affect the progress of tumor through DNA methylation, histone modification and miRNA regulation. In addition, statins can also achieve their anti-tumor effects by promoting tumor cell autophagy, regulating tumor cell cycle, and promoting tumor cell apoptosis and other signaling pathways. Therefore, the research on statins provides ideas for the discovery of new anti-tumor treatments. In this paper, the role of statins in the prevention and treatment of common tumors is reviewed, including its mechanism of inhibiting the occurrence and development of tumors through epigenetic regulation and other related mechanisms, as well as its clinical research status.

Key words

statins / cancer / epigenetics / clinical research / mevalonate pathway

引用本文

王媛茹, 李学军. 他汀类药物抗肿瘤作用的表观与非表观遗传调节及临床研究进展. 药学学报, 2023 , 58 (8) : 2146 -2154 . DOI: 10.16438/j.0513-4870.2023-0660

Yuan-ru WANG, Xue-jun LI. The epigenetic and non-epigenetic regulation of statins on its anti-tumor effect and its clinical research progress[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2146 -2154 . DOI: 10.16438/j.0513-4870.2023-0660

正文

收起

他汀类药物是HMG-CoA还原酶的竞争性抑制剂, HMG-CoA还原酶在内源性胆固醇合成的早期发生作用, 是胆固醇合成的限速酶。他汀类作为降胆固醇的药物, 广泛应用于预防和治疗心血管疾病。人类血浆胆固醇主要来自饮食的摄入或细胞生物合成, 他汀类药物通过降低新胆固醇生物合成和诱导低密度脂蛋白(low-density lipoprotein, LDL) 受体的表达来降低血浆胆固醇水平。而胆固醇作为哺乳动物细胞膜的关键结构, 许多胆固醇的代谢产物参与了细胞的增殖、细胞膜完整性、细胞信号传导、蛋白质合成和细胞周期等生物过程。

他汀类药物对黑色素瘤、乳腺癌、胰腺癌、神经胶质瘤、神经母细胞瘤和淋巴瘤等多种癌症有抑制作用^[1], 并在疾病发展的不同时间发挥不同的作用。在疾病发展初期, 有研究发现使用他汀类药物可显著降低胰腺癌患病风险^[2]。对于诊断为结直肠癌的患者及早期未发现癌症的患者而言, 使用他汀类药物可以延长患者生存期并降低患癌风险及死亡率^[3]。同样, 慢性阻塞性肺病(chronic obstructive pulmonary disease, COPD) 的患者相比于正常人更易患有肺癌, 一项研究显示^[4], COPD患者服用他汀类药物可使患肺癌的风险降低, 提示COPD患者可能从他汀类药物治疗中受益。

在疾病发展过程中, 他汀类药物与抗癌药物的联用能够降低不良反应的发生率, 并且得到更佳的治疗效果。在治疗肝细胞癌过程中, 他汀类药物与阿司匹林联合使用的临床效果显著, 并降低了食管静脉曲张患者静脉出血的风险^[5]。此外, 他汀类药物与程序性死亡受体1 (programmed cell death protein 1, PD-1) 抑制剂具有协同作用^[6], 并且在接受PD-1抑制剂治疗的非小细胞肺癌患者中, 他汀类药物以剂量依赖性方式产生更好的临床治疗效果。在进行手术治疗之后, 他汀类药物同样对癌症患者存在一定的保护作用, 一项研究纳入肝癌根治性切除术后患者进行统计, 结果显示他汀类药物的使用显著降低了肝癌复发的风险, 说明他汀类药物对肝癌根治性切除术后复发具有化学预防作用^[7]。在多项研究中, 他汀类药物能够降低乳腺癌患者的复发率和死亡率^{[8, 9]}。自20世纪90年代以来, 他汀类药物的抗肿瘤特性受到了广泛的关注。由于他汀类药物的安全性良好, 这类老药新用的研究比开发新药更便宜, 引起了人们的兴趣, 对其作用机制研究的兴趣也日益增多。然而他汀类药物是否具有抗肿瘤作用仍需进一步确定, 一项随机对照试验研究发现, 在预后小于2年的晚期癌症患者标准抗癌治疗中添加他汀类药物似乎不能改善总生存期或无进展生存期^[10]。一些观察性研究同样展现了矛盾的结果, 一部分结果表明他汀类药物使用降低了癌症风险^{[11, 12]}, 而另一些研究报告指出他汀类药物增加或没有影响癌症风险^{[13, 14]}。因此, 本文对他汀类药物的抗肿瘤作用和作用机制最新进展做一综述, 也关注其在表观遗传调节方面的机制和其抗肿瘤作用的临床研究现状。

1 他汀类药物抗肿瘤作用的表观遗传调节机制

收起

癌症的发生和发展是遗传或表观遗传改变的结果, 迄今已知的表观遗传调节包括DNA甲基化、组蛋白修饰和染色质重塑及非编码RNA调节基因表达等(表 1)。DNA高甲基化和肿瘤抑制基因的失活是肿瘤形成的治疗靶点, 他汀类常作为DNA去甲基化药物^[15]。在组蛋白修饰方面, 对组蛋白乙酰转移酶(histone acetyltransferase, HAT) 和组蛋白去乙酰化酶(histone deacetylase, HDAC) 的调节作用可能是他汀类药物促凋亡特性的基础。在非编码RNA方面, 微小核糖核酸(microRNA, miRNA) 也介导他汀类药物的一些抗肿瘤特性(图 1)。

1.1 对DNA甲基化的影响

DNA甲基化主要是通过DNA甲基转移酶(DNA methyltransferase, DNMT) 来实现的, 在哺乳动物体内表现为DNMTs将一个甲基从S-腺苷蛋氨酸转移到胞嘧啶的5'位置。异常的DNA甲基化通常被认为是癌症的标志。他汀类药物在体内常用作DNA去甲基化药物, 但这种生物活性在不同疾病中有不同的表现^[9]。如在结肠直肠癌细胞系中, 洛伐他汀以时间、剂量依赖的方式激活抑癌基因, 如骨形成蛋白(bone morphogenetic protein, BMP)。但也有报道认为洛伐他汀的去甲基化作用抵消了BMP2基因启动子的高甲基化产生的对肿瘤细胞的抑制作用^[16]。

1.2 组蛋白修饰

1.2.1 抑制EZH2, 延缓肿瘤生长

组蛋白赖氨酸N-甲基转移酶(enhancer of zeste homolog 2, EZH2) 编码的是一种组蛋白赖氨酸N-甲基转移酶, 它能够催化组蛋白H3第27位赖氨酸的甲基化(trimethylated histone H3 at lysine 27, H3K27Me3), 进而沉默下游多种抑癌基因, 从而导致肿瘤的生长。现有研究发现, 除普伐他汀外的他汀类药物均能下调结肠癌细胞的EZH2表达, 并诱导p27^Kip1的表达, 说明他汀类药物可能通过抑制EZH2介导的表观遗传学改变肿瘤进程, 从而提高结直肠癌的生存率^[17]。另有研究显示, 在肺癌组织中能观察到EZH2水平升高, 用辛伐他汀处理后能够剂量依赖性地抑制癌细胞的转移和EZH2的表达, 可能是辛伐他汀诱导了肺癌组织甲基转移酶3 (methyltransferase-like 3, METTL3) 下调, METTL3通过6-甲基腺嘌呤(N6-methyladenosine, m6A) 修饰A549细胞的mRNA来降低EZH2的表达, 从而抑制肿瘤的增殖^[18]。

1.2.2 抑制HDACs活性

他汀类药物对HATs和HDACs的调节作用可能是其促进肿瘤细胞凋亡的基础。他汀类药物主要抑制HDACs的活性, 对于HATs的影响目前研究较少。阿托伐他汀、氟伐他汀、洛伐他汀、普伐他汀和辛伐他汀能够抑制人A549肺癌细胞的HDACs活性并增加组蛋白H3的乙酰化^[19]。这些他汀类药物通过抑制HDAC 1和2, 使得p21启动子组蛋白H3乙酰化增加, 从而增加了细胞周期蛋白依赖性激酶抑制剂p21的mRNA表达, p21表达的增加会抑制肿瘤的增殖。此外, 辛伐他汀能够通过抑制HDAC1和Ras同源物家族成员A (Ras homolog family member A, RhoA) 的再激活, 减少3-甲基胆蒽在肾上皮细胞中的致癌作用^[20]。

Rimpelová等^[21]使用不同他汀类药物处理胰腺癌细胞(MiaPaCa2), 结果发现他汀类药物不改变编码HAT或HDAC基因的表达, 但编码组蛋白H4的基因下调, 而在西立伐他汀、匹伐他汀和辛伐他汀处理下, 编码组蛋白H2B的基因上调。另有研究发现, 辛伐他汀能够抑制HDAC2和HDAC5的活性, 并显著抑制了氧固醇结合蛋白相关蛋白5 (oxysterol binding related proteins 5, ORP5) 的转录, 该蛋白与胰腺癌细胞的转移性侵袭相关。Karlic等^[22]发现用辛伐他汀处理乳腺癌细胞和前列腺癌细胞, 二者细胞系中HDAC1、HDAC2、HDAC3、HDAC7和HDAC8 mRNA的水平均降低, 这可能会增加组蛋白乙酰化, 但没有证明辛伐他汀对HDAC活性、蛋白质表达或组蛋白乙酰化的影响。

在药物联合应用方面, 伏立诺他(HDAC抑制剂) 与氟伐他汀联用展现了良好的临床效果。伏立诺他通过激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 通路减弱了自身的抗癌活性, 而氟伐他汀可激活AMP依赖的蛋白激酶(adenosine 5-monophosphate-activated protein kinase, AMPK)。伏立诺他和氟伐他汀的组合在体外和体内均强烈诱导细胞凋亡并有效抑制肾癌细胞生长。伏立诺他激活mTOR通路, 而氟伐他汀通过激活AMPK来抑制这种磷酸化, 氟伐他汀还增强了伏立诺他诱导的组蛋白乙酰化。此外, 该组合诱导内质网应激, 并发现AMPK激活、组蛋白乙酰化和内质网应激诱导之间存在正反馈循环^[23]。

1.2.3 促进H2AX组蛋白的磷酸化

组蛋白H2AX在丝氨酸139 (γ-H2AX) 位点的磷酸化可能与DNA直接损伤或细胞代谢功能障碍有关^[24]。氟伐他汀在人多形胶质母细胞瘤细胞系(GBM-8401) 中促凋亡的潜在机制可能是促进H2AX组蛋白的磷酸化以及H3和H4组蛋白的乙酰化^[25]。

1.3 非编码RNA的调节

miRNAs介导他汀类药物的一些抗癌特性^[26]。丙氨酸氨基转移酶(alanine aminotransferase, ALT) 的增加是肝损伤的常见标志, Pek等^[27]认为miR-192可能是他汀类药物诱导肝损害的早期生物标志物。肝细胞性肝癌中miR-192和miR-21的增加与ALT的增加相关, 由此推测他汀类药物可能通过miR-192诱导肝癌细胞的凋亡; 洛伐他汀对miR-33b的增强作用与髓母细胞瘤细胞中c-myc表达的抑制有关^[28]; 阿托伐他汀对癌细胞系中的细胞周期具有类似的作用, 其能够分别通过miR-182和miR-124a调节p21和胍基乙酸N-甲基转移酶基因的表达; miR-182通过下调Bcl-2的表达促进细胞凋亡^[29]。有研究发现辛伐他汀能够改变各种癌细胞系中400多种miRNAs的表达^[30], 包括具有抗癌活性的miR-612, 它能够促进癌细胞分化, 增加其化学敏感性。

他汀类药物通过影响DNMTs激活抑癌基因; 通过影响一些miRNAs的活性影响肿瘤细胞的增殖和分化; 在组蛋白修饰方面, 他汀类药物影响一些组蛋白的乙酰化或磷酸化, 从而诱导肿瘤细胞的凋亡。

2 他汀类药物抗肿瘤作用的非表观遗传调节机制

收起

通常癌细胞表现出脂质代谢途径的改变, 如伴有过多的脂肪生成和胆固醇合成。他汀类药物抑制胆固醇的合成主要是通过甲羟戊酸(mevalonic acid, MVA)途径。靶向抑制MVA途径在抑制肿瘤细胞的生长中起一定的作用, 他汀类药物在大量研究中被证实具有直接的抗肿瘤作用, 并通过抑制HMG-CoA还原酶以及相关信号途径抑制肿瘤的生长和转移(图 2)。他汀类药物还能通过影响一些蛋白的异戊烯化来抑制肿瘤细胞的增殖和迁移。一些临床前证据表明, 他汀类药物可以抑制肿瘤生长并诱导细胞凋亡^[31]。

2.1 促进肿瘤细胞凋亡和自噬

肿瘤细胞的凋亡和自噬能够有效地抑制肿瘤的生长。阿托伐他汀能够通过Ras同源物家族成员B (Ras homolog family member B, RhoB) 下调PTEN/Akt通路, 从而促进乳腺癌细胞凋亡^[32]。辛伐他汀通过抑制B淋巴细胞瘤-2 (B-cell lymphoma-2, Bcl-2) 的表达从而抑制乳腺癌细胞增殖。一些他汀类药物可降低前列腺细胞增殖并诱导细胞凋亡, 可能是通过下调前列腺癌细胞中Akt/FOXO1磷酸化介导的^[33]。另一研究联合使用阿托伐他汀和咖啡因, 发现其下调了Akt、Bcl-2和Survivin水平^[34], 进而促进了前列腺癌细胞的凋亡。阿托伐他汀通过诱导caspase-3和PARP (poly ADP-ribose polymerase) 激活并上调Bim, 降低细胞活力并促进子宫颈癌细胞的凋亡^[35]。

自噬与肿瘤的密切相关, 干预自噬是提高临床抗癌治疗效果的一种合理治疗策略, 而对于他汀类药物影响肿瘤细胞自噬的研究目前较少。现有研究发现他汀类药物通过GGPP合成酶1 (geranylgeranyl diphosphate synthase 1, GGPS1)-RAB7A自噬轴诱导了氧化应激累积和细胞凋亡 ^[36]。高浓度他汀类药物处理胰腺癌细胞后^[37], 其显著抑制了细胞周期蛋白A2 (cyclin A2, CCNA2) 相关DNA复制途径, 并上调了参与核糖体和自噬途径的基因。辛伐他汀能够显著抑制胰腺癌细胞的迁移、侵袭和基质金属蛋白酶(matrix metalloproteinase, MMP)-2/MMP-9的表达^[38]。阿托伐他汀能够以剂量依赖的形式上调自噬标志物LC3-Ⅱ的表达水平, 进而诱导前列腺癌细胞的自噬和自噬相关细胞的死亡^[39]。同样, 阿托伐他汀诱导宫颈癌细胞自噬, 阿托伐他汀联合自噬蛋白酶抑制剂与单独使用阿托伐他汀相比显著增强了阿托伐他汀诱导的宫颈癌细胞凋亡和自噬。综上, 他汀类药物能够调节部分肿瘤细胞的凋亡和自噬, 然而其对凋亡和自噬调控的机制仍需要进一步探索。

2.2 调节细胞周期

他汀类药物通过调节细胞周期相关蛋白以及蛋白依赖性激酶, 来实现肿瘤细胞增殖的抑制作用。一方面, 阿托伐他汀增强细胞周期蛋白p21的mRNA表达, 从而抑制肺癌细胞的增殖, 可能与前述他汀类药物的表观遗传调节机制相关。洛伐他汀与曲格列酮联合应用, 可通过上调细胞周期蛋白p21^cip和p27^kip的表达, 使甲状腺癌细胞在G0/G1期发生细胞周期阻滞, 还可抑制甲状腺癌细胞G1/S期的进展, 进而抑制肿瘤细胞的生长^[40]。另一方面, 高浓度的洛伐他汀抑制以CCNA2为基础的细胞周期通路, 显著抑制胰腺癌细胞的增殖。此外, 辛伐他汀通过下调细胞周期蛋白D1 (cyclin D1, CCND1) 和细胞周期蛋白依赖性激酶(cyclin-dependent kinases, CDKs) 的表达诱导乳腺癌细胞凋亡^[41]。

2.3 抑制NF-κB活性以及相关蛋白的活性

核因子κB (nuclear factor kappa-B, NF-κB) 在肿瘤的起始和进展中发挥着重要的作用。研究发现, NF-κB有助于肿瘤的发展, 包括促进转移、使血管生成、改变肿瘤微环境和避免凋亡等^[42]。辛伐他汀通过抑制NF-κB的活化来降低MMP-2的表达, 通过抑制NF-κB和LIN28B并上调let-7 miRNA显著抑制去势抵抗性前列腺癌细胞的生长, 并与NF-κB抑制剂联用协同诱导凋亡, 抑制前列腺癌细胞的生长^[43]。同样, 有相关研究发现^[44], 阿托伐他汀联合塞来昔布和替皮法尼布可以抑制CD44、CD133、乙醛脱氢酶1A1 (acetaldehyde dehydrogenase-1A1, ALDH1A)、Akt和NF-κB的活化, 从而降低胰腺癌细胞的成球能力, 并能明显抑制成球细胞的增殖、促进肿瘤干细胞凋亡。

2.4 抑制PI3K/Akt信号通路

磷脂酰肌醇3激酶(phosphoinositide 3-kinase, PI3K) 信号参与多种细胞信号的调节, 包括其下游分子Akt组成的信号通路均与肿瘤的进展相关。2012年一项实验发现他汀类药物通过调节PI3K/Akt信号通路, 显著延缓了胰腺上皮内肿瘤向胰腺癌的发展^[45]。另外, 他汀类药物可以通过抑制PI3K/Akt信号传导来抑制乳腺癌细胞的生长^[46]。

最近一项研究^[47]发现他汀类药物在结直肠癌中能够诱导磷酸酯酶与张力蛋白同源物(phosphatase and tensin homolog, PTEN) 活性的上调和BMP特异性激活, 从而抑制PI3K/Akt/mTOR信号传导。阿托伐他汀通过RhoB下调PTEN/Akt通路, 从而促进乳腺癌细胞凋亡^[32]。辛伐他汀或氟伐他汀可降低前列腺细胞增殖并诱导细胞凋亡, 是通过下调前列腺癌细胞中Akt/FOXO1磷酸化介导的^[33]。

2.5 抑制MEK/ERK信号通路

MEK/ERK信号通路与肿瘤密切相关。研究发现, 肝细胞癌进程中LDLR下调, 可能是通过刺激MEK/ERK信号通路导致的。胆固醇与LDLR结合能够使大部分循环中的胆固醇供肝细胞利用。LDLR下调使得肝细胞内胆固醇合成增多, 加速了肝细胞癌细胞的增殖。他汀类药物作为HMG-CoA抑制剂能够抑制细胞内胆固醇的合成, 从而抑制肝细胞癌细胞的增殖^[48]。奥沙利铂作为烷化化疗药物, 常导致周围神经病变等不良反应。在结直肠癌中, 辛伐他汀通过活化体内ERK1/2增强了奥沙利铂的抗肿瘤作用, 抑制了奥沙利铂诱导的神经病变^[49]。

2.6 抑制JAK2/STAT3信号通路

JAK2/STAT3信号通路能够促进炎症反应。同样, 它在肿瘤的转移、肿瘤细胞的凋亡和血管生成中起重要的作用^[50]。有研究发现, 他汀类药物能诱导肾细胞凋亡的机制可能是抑制了JAK2/STAT3信号通路^[51], 它显著抑制了A498细胞的增殖、迁移和侵袭。STAT蛋白的失活主要由细胞因子信号传导抑制蛋白(suppressor of cytokine signaling, SOCS) 的表达调节, 辛伐他汀处理骨肉瘤细胞后SOCS-3的表达增加, 进而降低JAK2和STAT5的磷酸化水平, 其浓度依赖性地抑制骨肉瘤细胞的增殖、迁移和侵袭^[52]。

2.7 调节Kv1.3通路

电压门控钾离子通道是完整的膜蛋白, 在质膜和线粒体内膜中都发现了Kv1.3, 可选择性渗透钾离子并在膜电位改变时被激活。Kv1.3通道是某些癌症在内的潜在分子靶标。Kv1.3通道的亲脂性有机抑制剂可能会在临床上应用于某些疾病的治疗, 如乳腺癌、胰腺癌和肺癌等。目前有研究表明^[53], 他汀类药物是癌细胞中电压门控钾通道Kv1.3的抑制剂。并且在1.5~50 µmol·L^-1范围内应用他汀类药物会以浓度依赖性方式抑制该通道, 但不同他汀类药物的抑制作用不同, 以辛伐他汀作用最好, 这也许是他汀类药物治疗乳腺癌的机制之一。

3 他汀类药物抗肿瘤作用的临床研究

收起

现如今许多他汀类药物的抗肿瘤作用已进入临床研究阶段, 截止2023年www.clinicaltrials.gov注册的、正在进行的他汀类药物抗肿瘤临床试验汇总见表 2, 目前已发表他汀类药物抗肿瘤作用临床研究的文章较少, 包括他汀类药物与化疗药物、其他抗肿瘤药物联合的临床抗肿瘤作用研究, 表 2^[54-64]中只展现单独使用他汀类药物对肿瘤患者的影响。他汀类药物在大部分抗肿瘤的临床试验中, 能够改善癌症患者的生存期及肿瘤微环境。部分试验组与安慰剂组无明显差异的原因可能是纳入患者的数量较少、剂量使用差异等。

近年来他汀类药物作为抗肿瘤药物的临床试验也逐步增加, 从2018~2023年正在进行的他汀类药物抗肿瘤临床试验汇总见表 3。他汀类药物单独作为抗肿瘤药物的应用逐渐增多, 因此他汀类药物在临床抗肿瘤作用方面有一定的应用前景。

4 总结与展望

收起

越来越多的证据表明, 他汀类药物除了降血脂作用之外, 还可能具有更多广泛的作用, 是多靶点药物。本综述主要阐述了他汀类药物与其抗肿瘤的作用及其机制, 包括表观遗传调节特性。表观遗传机制在细胞发育和具体功能中起着重要作用, 他汀类药物可以在不同类型的细胞中改变表观遗传调节作用。但现有研究主要都是关于他汀类药物与心血管疾病之间的表观修饰特性, 与肿瘤相关的研究较少并且确切的潜在分子机制尚未阐明。关于他汀类药物能够降低癌症的发病率、死亡风险的研究主要都是通过meta分析展现的, 对于其机制的研究较少。

值得注意的是, 他汀类药物对肿瘤的进展是否有益处, 仍存在一定的争议。一项统计性研究表示^[21], 他汀类药物的使用与癌症死亡率没有相关性, 在癌症确诊后6个月内使用他汀类药物治疗, 并不能提高3年内癌症特异性或总体生存率。另一项研究结果^[65]表明, 他汀类药物可能不抑制表观遗传修饰酶, 即HDACs、HATs和DNMTs, 反而会增加DNMT的活性。对于活细胞和核提取物中多种细胞类型的HDAC活性和使用两种不同的HDAC底物的综合研究表明, 他汀类药物的治疗无效。虽然体外研究表明他汀类药物不太可能直接抑制这些表观遗传酶, 但在药物的长期治疗和细胞代谢的影响下, 他汀类药物可能间接影响这些表观遗传酶。因此他汀类药物可能通过表观遗传的方式影响特定基因的表观遗传修饰, 从而影响基因的表达。

综上所述, 他汀类药物是一种潜在的抗肿瘤药物, 但是否有利于肿瘤性疾病的防治, 有待进一步的研究证实。此外, 不同类别的他汀类药物抗肿瘤作用机制各不相同, 其抗肿瘤作用机制和潜在靶点仍需要长期研究, 以促进其更加精准、个性化的使用。

作者贡献: 王媛茹负责文献检索和文章撰写; 李学军负责指导论文写作与修改, 对整体结构和质量进行把控。

利益冲突: 本研究内容无任何经济利益或版权冲突。

基金

收起

国家自然科学基金资助项目(81673453)
国家自然科学基金资助项目(82073878)
国家自然科学基金资助项目(81874318)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

Jakobisiak M, Golab J. Potential antitumor effects of statins[J]. Int J Oncol, 2003, 23: 1055-1069.

[2]

Zhang Y, Liang MM, Sun CY, et al. Statin use and risk of pancreatic cancer an updated meta-analysis of 26 studies[J]. Pancreas, 2019, 48: 142-150.

https://doi.org/10.1097/MPA.0000000000001226

[3]

Qi JH, Wei JN, Zhang ZJ, et al. A meta-analysis on association between statins and colorectal cancer[J]. Chin J Epidemiol (中华流行病学杂志), 2021, 42: 343-350.

[4]

Raymakers A, Sin DD, Sadatsafavi M, et al. Statin use and lung cancer risk in chronic obstructive pulmonary disease patients: a population-based cohort study[J]. Respir Res, 2020, 21: 118.

https://doi.org/10.1186/s12931-020-01344-w

[5]

Singh J, Wozniak A, Cotler SJ, et al. Combined use of aspirin and statin is associated with a decreased incidence of hepatocellular carcinoma[J]. J Clin Gastroenterol, 2022, 56: 369-373.

https://doi.org/10.1097/MCG.0000000000001546

[6]

Cantini L, Pecci F, Hurkmans DP, et al. High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients[J]. Eur J Cancer, 2021, 144: 41-48.

https://doi.org/10.1016/j.ejca.2020.10.031

[7]

Yang SY, Wang CC, Chen KD, et al. Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma[J]. BMC Cancer, 2021, 21: 70.

https://doi.org/10.1186/s12885-021-07796-7

[8]

Mansourian M, Haghjooy-Javanmard S, Eshraghi A, et al. Statins use and risk of breast cancer recurrence and death: a systematic review and meta-analysis of observational studies[J]. J Pharm Pharm Sci, 2016, 19: 72-81.

https://doi.org/10.18433/J3202B

[9]

Borgquist S, Bjarnadottir O, Kimbung S, et al. Statins: a role in breast cancer therapy?[J]. J Intern Med, 2018, 284: 346-357.

https://doi.org/10.1111/joim.12806

[10]

Farooqi MAM, Malhotra N, Mukherjee SD, et al. Statin therapy in the treatment of active cancer: a systematic review and meta-analysis of randomized controlled trials[J]. PLoS One, 2018, 13: e0209486.

https://doi.org/10.1371/journal.pone.0209486

[11]

Beck P, Wysowski DK, Downey W, et al. Statin use and the risk of breast cancer[J]. J Clin Epidemiol, 2003, 56: 280-285.

https://doi.org/10.1016/S0895-4356(02)00614-5

[12]

Undela K, Srikanth V, Bansal D. Statin use and risk of breast cancer: a meta-analysis of observational studies[J]. Breast Cancer Res Treat, 2012, 135: 261-269.

https://doi.org/10.1007/s10549-012-2154-x

[13]

Chae YK, Valsecchi ME, Kim J, et al. Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins[J]. Cancer Invest, 2011, 29: 585-593.

https://doi.org/10.3109/07357907.2011.616252

[14]

Chang WT, Lin HW, Lin SH, et al. Association of statin use with cancer- and noncancer-associated survival among patients with breast cancer in Asia[J]. JAMA Netw Open, 2023, 6: e239515.

https://doi.org/10.1001/jamanetworkopen.2023.9515

[15]

Makino N, Maeda T, Abe N. Short telomere subtelomeric hypomethylation is associated with telomere attrition in elderly diabetic patients[J]. Can J Physiol Pharmacol, 2019, 97: 335-339.

https://doi.org/10.1139/cjpp-2018-0568

[16]

Kodach LL, Jacobs RJ, Voorneveld PW, et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway[J]. Gut, 2011, 60: 1544-1553.

https://doi.org/10.1136/gut.2011.237495

[17]

Ishikawa S, Hayashi H, Kinoshita K, et al. Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer[J]. Int J Cancer, 2014, 135: 2528-2536.

https://doi.org/10.1002/ijc.28672

[18]

Chen WW, Qi JW, Hang Y, et al. Simvastatin is beneficial to lung cancer progression by inducing METTL3-induced m6A modification on EZH2 mRNA[J]. Eur Rev Med Pharmacol Sci, 2020, 24: 4263-4270.

[19]

Sarker H, Haimour A, Toor R, et al. The emerging role of epigenetic mechanisms in the causation of aberrant MMP activity during human pathologies and the use of medicinal drugs[J]. Biomolecules, 2021, 11: 578.

https://doi.org/10.3390/biom11040578

[20]

Chang CC, Huang KH, Hsu SP, et al. Simvastatin reduces the carcinogenic effect of 3-methylcholanthrene in renal epithelial cells through histone deacetylase 1 inhibition and RhoA reactivation[J]. Sci Rep, 2020, 10: 12526.

https://doi.org/10.1038/s41598-020-69592-w

[21]

Rimpelová S, Kolar M, Strnad H, et al. Comparison of transcriptomic profiles of MiaPaCa-2 pancreatic cancer cells treated with different statins[J]. Molecules, 2021, 26: 3528.

https://doi.org/10.3390/molecules26123528

[22]

Karlic H, Thaler R, Gerner C, et al. Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells[J]. Cancer Genet, 2015, 208: 241-252.

https://doi.org/10.1016/j.cancergen.2015.03.008

[23]

Okubo K, Isono M, Miyai K, et al. Fluvastatin potentiates anticancer activity of vorinostat in renal cancer cells[J]. Cancer Sci, 2020, 111: 112-126.

https://doi.org/10.1111/cas.14225

[24]

Suzuki S, Gi M, Toyoda T, et al. Role of gamma-H2AX as a biomarker for detection of bladder carcinogens in F344 rats[J]. J Toxicol Pathol, 2020, 33: 279-285.

https://doi.org/10.1293/tox.2020-0038

[25]

Chang YL, Huang LC, Chen YC, et al. The synergistic effects of valproic acid and fluvastatin on apoptosis induction in glioblastoma multiforme cell lines[J]. Int J Biochem Cell Biol, 2017, 92: 155-163.

https://doi.org/10.1016/j.biocel.2017.10.003

[26]

Mohammadzadeh N, Montecucco F, Carbone F, et al. Statins: epidrugs with effects on endothelial health?[J]. Eur J Clin Invest, 2020, 50: e13388.

https://doi.org/10.1111/eci.13388

[27]

Pek SLT, Tavintharan S, Woon K, et al. MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo-controlled study of simvastatin and ubiquinol supplementation[J]. Exp Biol Med, 2016, 241: 317-330.

https://doi.org/10.1177/1535370215605588

[28]

Takwi AA, Li Y, Becker Buscaglia LE, et al. A statin-regulated microRNA represses human c-Myc expression and function[J]. EMBO Mol Med, 2012, 4: 896-909.

https://doi.org/10.1002/emmm.201101045

[29]

Peng XJ, Li WP, Yuan L, et al. Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21[J]. PLoS One, 2013, 8: e70442.

https://doi.org/10.1371/journal.pone.0070442

[30]

Allen SC, Mamotte CDS. Pleiotropic and adverse effects of statins-do epigenetics play a role?[J]. J Pharmacol Exp Ther, 2017, 362: 319-326.

https://doi.org/10.1124/jpet.117.242081

[31]

Ahmadi M, Amiri S, Pecic S, et al. Pleiotropic effects of statins: a focus on cancer[J]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866: 165968.

https://doi.org/10.1016/j.bbadis.2020.165968

[32]

Ma Q, Gao Y, Xu P, et al. Atorvastatin inhibits breast cancer cells by downregulating PTEN/AKT pathway via promoting Ras homolog family member B (RhoB)[J]. Biomed Res Int, 2019, 2019: 3235021.

[33]

Deng JL, Zhang R, Zeng Y, et al. Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells[J]. Cancer Manag Res, 2019, 11: 7231-7242.

https://doi.org/10.2147/CMAR.S212643

[34]

Wang ZS, Zhang LY, Wan Z, et al. Atorvastatin and caffeine in combination regulates apoptosis, migration, invasion and tumorspheres of prostate cancer cells[J]. Pathol Oncol Res, 2020, 26: 209-216.

https://doi.org/10.1007/s12253-018-0415-7

[35]

Sheng B, Song YZ, Zhang JA, et al. Atorvastatin suppresses the progression of cervical cancer via regulation of autophagy[J]. Am J Transl Res, 2020, 12: 5252-5268.

[36]

Guo CC, Wan RJ, He YY, et al. Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer[J]. Nat Cancer, 2022, 3: 614.

https://doi.org/10.1038/s43018-022-00358-1

[37]

Chen C, Wu HJ, Kong DSY, et al. Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer[J]. Oncol Rep, 2020, 44: 2569-2580.

https://doi.org/10.3892/or.2020.7810

[38]

Shen YJ, Li MM, Sun F, et al. Low-dose photodynamic therapy-induced increase in the metastatic potential of pancreatic tumor cells and its blockade by simvastatin[J]. J Photochem Photobiol B, 2020, 207: 111889.

https://doi.org/10.1016/j.jphotobiol.2020.111889

[39]

Parikh A, Childress C, Deitrick K, et al. Statin-induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells[J]. Prostate, 2010, 70: 971-981.

https://doi.org/10.1002/pros.21131

[40]

Zhong WB, Tsai YC, Chin LH, et al. A synergistic anti-cancer effect of troglitazone and lovastatin in a human anaplastic thyroid cancer cell line and in a mouse xenograft model[J]. Int J Mol Sci, 2018, 19: 1834.

https://doi.org/10.3390/ijms19071834

[41]

Shen YY, Yuan Y, Du YY, et al. Molecular mechanism underlying the anticancer effect of simvastatin on MDA-MB-231 human breast cancer cells[J]. Mol Med Rep, 2015, 12: 623-630.

https://doi.org/10.3892/mmr.2015.3411

[42]

Motolani A, Martin M, Sun MY, et al. Phosphorylation of the regulators, a complex facet of NF-κB signaling in cancer[J]. Biomolecules, 2021, 11: 15.

[43]

Kang M, Lee KH, Lee HS, et al. Concurrent treatment with simvastatin and NF-κB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anticancer effects via control of the NF-κB/LIN28/let-7 miRNA signaling pathway[J]. PLoS One, 2017, 12: e0184644.

https://doi.org/10.1371/journal.pone.0184644

[44]

Xu XT, Chen J, Ren X, et al. Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere-forming cells[J]. Eur J Pharmacol, 2021, 893: 173840.

https://doi.org/10.1016/j.ejphar.2020.173840

[45]

Mohammed A, Qian L, Janakiram NB, et al. Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48^Cre/+. LSL-Kras^G12D/+ mice[J]. Int J Cancer, 2012, 131: 1951-1962.

https://doi.org/10.1002/ijc.27456

[46]

Beckwitt CH, Shiraha K, Wells A. Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling[J]. PLoS One, 2018, 13: e0197422.

https://doi.org/10.1371/journal.pone.0197422

[47]

Ouahoud S, Jacobs RJ, Peppelenbosch MP, et al. Kinome-wide analysis of the effect of statins in colorectal cancer[J]. Br J Cancer, 2021, 124: 1978-1987.

https://doi.org/10.1038/s41416-021-01318-9

[48]

Chen ZY, Chen L, Sun B, et al. LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway[J]. Mol Metab, 2021, 51: 101230.

https://doi.org/10.1016/j.molmet.2021.101230

[49]

Tsubaki M, Takeda T, Matsuda T, et al. Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy[J]. Cancer Cell Int, 2023, 23: 73.

https://doi.org/10.1186/s12935-023-02884-z

[50]

Yu H, Jove R. The stats of cancer - new molecular targets come of age[J]. Nat Rev Cancer, 2004, 4: 97-105.

https://doi.org/10.1038/nrc1275

[51]

Fang ZQ, Tang YQ, Fang JJ, et al. Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway[J]. PLoS One, 2013, 8: e62823.

https://doi.org/10.1371/journal.pone.0062823

[52]

Sandoval-Usme MC, Umana-Perez A, Guerra B, et al. Simvastatin impairs growth hormone-activated signal transducer and activator of transcription (STAT) signaling pathway in UMR-106 osteosarcoma cells[J]. PLoS One, 2014, 9: e87769.

https://doi.org/10.1371/journal.pone.0087769

[53]

Teisseyre A, Uryga A, Michalak K. Statins as inhibitors of voltage-gated potassium channels Kv1.3 in cancer cells[J]. J Mol Struct, 2021, 1230: 129905.

https://doi.org/10.1016/j.molstruc.2021.129905

[54]

Marlatt KL, Steinberger J, Rudser KD, et al. The effect of atorvastatin on vascular function and structure in young adult survivors of childhood cancer: a randomized, placebo-controlled pilot clinical trial[J]. J Adolesc Young Adult Oncol, 2019, 8: 442-450.

https://doi.org/10.1089/jayao.2017.0075

[55]

Raittinen PVH, Syvala H, Tammela TLJ, et al. Atorvastatin induces adrenal androgen downshift in men with prostate cancer: a post Hoc analysis of a pilot adaptive randomised clinical trial[J]. EBioMedicine, 2021, 68: 103432.

https://doi.org/10.1016/j.ebiom.2021.103432

[56]

Jeong IG, Lim B, Yun SC, et al. Adjuvant low-dose statin use after radical prostatectomy: the PRO-STAT randomized clinical trial[J]. Clin Cancer Res, 2021, 27: 5004-5011.

https://doi.org/10.1158/1078-0432.CCR-21-0480

[57]

Fernandez KA, Allen P, Campbell M, et al. Atorvastatin is associated with reduced cisplatin-induced hearing loss[J]. J Clin Invest, 2021, 131: e142616.

https://doi.org/10.1172/JCI142616

[58]

Garwood ER, Kumar AS, Baehner FL, et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer[J]. Breast Cancer Res Treat, 2010, 119: 137-144.

https://doi.org/10.1007/s10549-009-0507-x

[59]

Kawata S, Yamasaki E, Nagase T, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial[J]. Br J Cancer, 2001, 84: 886-891.

https://doi.org/10.1054/bjoc.2000.1716

[60]

Singh PP, Lemanu DP, Soop M, et al. Perioperative simvastatin therapy in major colorectal surgery: a prospective, double-blind randomized controlled trial[J]. J Am Coll Surg, 2016, 223: 308.

https://doi.org/10.1016/j.jamcollsurg.2016.04.004

[61]

Schmidmaier R, Baumann P, Simsek M, et al. The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase[J]. Blood, 2004, 104: 1825-1832.

[62]

Lazzeroni M, Guerrieri-Gonzaga A, Serrano D, et al. Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase Ⅱ clinical trial with nimesulide, simvastatin and placebo[J]. BMC Cancer, 2012, 12: 575.

https://doi.org/10.1186/1471-2407-12-575

[63]

Higgins MJ, Prowell TM, Blackford AL, et al. A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer[J]. Breast Cancer Res Treat, 2012, 131: 915-924.

https://doi.org/10.1007/s10549-011-1858-7

[64]

Atochina-Vasserman EN, Goncharov DA, Volgina AV, et al. Statins in lymphangioleiomyomatosis simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling[J]. Am J Respir Cell Mol Biol, 2013, 49: 704-709.

https://doi.org/10.1165/rcmb.2013-0203RC

[65]

Bridgeman S, Northrop W, Ellison G, et al. Statins do not directly inhibit the activity of major epigenetic modifying enzymes[J]. Cancers, 2019, 11: 516.

https://doi.org/10.3390/cancers11040516

2023年第58卷第8期

PDF下载

737

418

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2023-0660

接收时间：2023-05-24
首发时间：2025-11-21
出版时间：2023-08-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2023-05-24
修回日期：2023-06-05

基金

国家自然科学基金资助项目(81673453)

国家自然科学基金资助项目(82073878)

国家自然科学基金资助项目(81874318)

作者信息

1.石河子大学药学院, 新疆石河子 832000

2.北京大学医学部基础医学院, 北京 100191

通讯作者:

*李学军, Tel: 86-10-82801421, E-mail: xjli@bjmu.edu.cn

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2023-0660

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Cancer type	Type of statins	Cell line	Mechanism
Colorectal cancer	All statins except pravastatin	DLD1/HT29/SW620/HCT116	EZH2
Lung cancer	Simvastatin/atorvastatin/lovastatin	A549	HDACs
Simvastatin	A549	MetT13/EZH2
Hepatocarcinoma	Simvastatin	HepG2	miR-192
Pancreatic cancer	Simvastatin	MiaPaCa2	HDAC1/5
Prostatic cancer	Simvastatin	PC3	HDACs
Renal carcinoma	Atorvastatin	-	HDACs
Glioma	Fluvastatin	GBM-8401	H2AX/H3/H4

Cancer type

Type of statins

Cell line

Mechanism

Colorectal cancer

All statins except pravastatin

DLD1/HT29/SW620/HCT116

EZH2

Lung cancer

Simvastatin/atorvastatin/lovastatin

A549

HDACs

Simvastatin

A549

MetT13/EZH2

Hepatocarcinoma

Simvastatin

HepG2

miR-192

Pancreatic cancer

Simvastatin

MiaPaCa2

HDAC1/5

Prostatic cancer

Simvastatin

PC3

HDACs

Renal carcinoma

Atorvastatin

HDACs

Glioma

Fluvastatin

GBM-8401

H2AX/H3/H4

Statin type	Cancer type	Research type	Number of patients	Dosage	Result	Ref
Atorvastatin	Non-Hodgkin lymphoma	Clinical trial	27	40 mg·d^-1, 6 months	The vascular endothelial function improved after treatment	[54]
	Prostatic cancer	Randomized control	160	80 mg·d^-1, 3-5 weeks	Inducing the decrease of adrenal androgen in men with prostate cancer	[55]
	Prostatic cancer	Clinical trial	364	20 mg·d^-1, 1 year	There was no significant difference in testosterone and sex hormone binding globulin levels between groups	[56]
	Squamous cell carcinoma of head and neck	Clinical trial	32	10-80 mg·d^-1, 4 weeks	Atorvastatin use was significantly associated with cisplatin-induced hearing loss reduction	[57]
Fluvastatin	Breast cancer	Clinical trial	35	20, 80 mg·d^-1, 6 weeks	Reduce tumor proliferation and increase apoptosis activity in high-grade breast cancer	[58]
Pravastatin	Hepatocarcinoma	Randomized control	91	40 mg·d^-1, 2 months	The median survival time of pravastatin group was 18 months, while that of control group was 9 months	[59]
Simvastatin	Intestinal cancer	Randomized control	132	40 mg·d^-1, 3 weeks	The plasma concentrations of IL-6, IL-8 and TNFα and the peritoneal concentrations of IL-6 and IL-8 decreased significantly after operation	[60]
	Multiple myeloma	Phase Ⅱ clinic	30	80 mg·d^-1, consistent with the course of chemotherapy	HMG-CoA/GG-PP/Rho/Rho kinase pathway mediates CAM-DR, and statins target this pathway to improve the efficacy of anti-myeloma treatment	[61]
	Breast cancer	Randomized control	150	20 mg·d^-1, 1 year	Compared with the placebo group, there was no obvious adverse reaction	[62]
	Breast cancer	Phase Ⅱ clinic	50	40 mg·d^-1, 6-7 months	The concentration of estrone sulfate decreased after simva-statin treatment, especially in postmenopausal subjects	[63]
	Lymphatic leiomyoma	Clinical trial	10	20-40 mg·d^-1, 4 months	Effects of simvastatin on growth inhibition and apoptosis promotion of TSC2-null cells	[64]

Statin type

Cancer type

Research type

Number of patients

Dosage

Result

Ref

Atorvastatin

Non-Hodgkin lymphoma

Clinical trial

40 mg·d^-1, 6 months

The vascular endothelial function improved after treatment

[54]

Prostatic cancer

Randomized control

160

80 mg·d^-1, 3-5 weeks

Inducing the decrease of adrenal androgen in men with prostate cancer

[55]

Prostatic cancer

Clinical trial

364

20 mg·d^-1, 1 year

There was no significant difference in testosterone and sex hormone binding globulin levels between groups

[56]

Squamous cell carcinoma of head and neck

Clinical trial

10-80 mg·d^-1, 4 weeks

Atorvastatin use was significantly associated with cisplatin-induced hearing loss reduction

[57]

Fluvastatin

Breast cancer

Clinical trial

20, 80 mg·d^-1, 6 weeks

Reduce tumor proliferation and increase apoptosis activity in high-grade breast cancer

[58]

Pravastatin

Hepatocarcinoma

Randomized control

40 mg·d^-1, 2 months

The median survival time of pravastatin group was 18 months, while that of control group was 9 months

[59]

Simvastatin

Intestinal cancer

Randomized control

132

40 mg·d^-1, 3 weeks

The plasma concentrations of IL-6, IL-8 and TNFα and the peritoneal concentrations of IL-6 and IL-8 decreased significantly after operation

[60]

Multiple myeloma

Phase Ⅱ clinic

80 mg·d^-1, consistent with the course of chemotherapy

HMG-CoA/GG-PP/Rho/Rho kinase pathway mediates CAM-DR, and statins target this pathway to improve the efficacy of anti-myeloma treatment

[61]

Breast cancer

Randomized control

150

20 mg·d^-1, 1 year

Compared with the placebo group, there was no obvious adverse reaction

[62]

Breast cancer

Phase Ⅱ clinic

40 mg·d^-1, 6-7 months

The concentration of estrone sulfate decreased after simva-statin treatment, especially in postmenopausal subjects

[63]

Lymphatic leiomyoma

Clinical trial

20-40 mg·d^-1, 4 months

Effects of simvastatin on growth inhibition and apoptosis promotion of TSC2-null cells

[64]

Statin type	Cancer type	Clinical trial number	Progress	Number of participants	Dosage	Time
Atorvastatin	Prostatic cancer	NCT03819101	Ⅲ	1 210	80 mg·d^-1	2019.6.6
	Prostatic cancer	NCT04026230	Ⅲ	400	80 mg·d^-1	2019.8.15
	Prostatic cancer	NCT03830164	Ⅱ	270	Once a day for six weeks, and three times a day for one year after no obvious abnormality	2019.11.20
	Breast cancer	NCT03872388	Ⅱ	80	20, 80 mg·d^-1	2019.1.14
	Breast cancer	NCT04601116	Ⅲ	3 360	80 mg·d^-1, 2 years	2021.1.4
	Breast cancer	NCT05103644	Ⅱ	60	80 mg·d^-1	2021.10.30
	Hemangioma	NCT02603328	Ⅰ+Ⅱ	80	80 mg·d^-1	2018.7.17
Pravastatin	Breast cancer	NCT04385433	Ⅲ	400	40 mg·d^-1, 1 year	2020.12.4
Rosuvastatin	Breast cancer	NCT05338723	Ⅲ	50	20 mg·d^-1, 6 months	2020.9.15
Simvastatin	Ovarian cancer	NCT04457089	Ⅰ	20	40 mg·d^-1, 6 months	2021.1.25
	Breast cancer	NCT03454529	Ⅱ	24	40 mg·d^-1, 2-4 weeks	2018.3.9
	Breast cancer	NCT03971019	Ⅲ	314	20 mg·d^-1	2019.3.28
	Breast cancer	NCT05550415	Ⅱ	26	40 mg·d^-1, 21 days	2022.8.19
	Pancreatic cancer	NCT03889795	Ⅰ	15	5, 20, 40 mg·d^-1	2019.6.5
	Hysteromyoma	NCT03400826	Ⅱ	60	40 mg·d^-1, 12 weeks	2018.8.20

Statin type

Cancer type

Clinical trial number

Progress

Number of participants

Dosage

Time

Atorvastatin

Prostatic cancer

NCT03819101

Ⅲ

1 210

80 mg·d^-1

2019.6.6

Prostatic cancer

NCT04026230

Ⅲ

400

80 mg·d^-1

2019.8.15

Prostatic cancer

NCT03830164

Ⅱ

270

Once a day for six weeks, and three times a day for one year after no obvious abnormality

2019.11.20

Breast cancer

NCT03872388

Ⅱ

20, 80 mg·d^-1

2019.1.14

Breast cancer

NCT04601116

Ⅲ

3 360

80 mg·d^-1, 2 years

2021.1.4

Breast cancer

NCT05103644

Ⅱ

80 mg·d^-1

2021.10.30

Hemangioma

NCT02603328

Ⅰ+Ⅱ

80 mg·d^-1

2018.7.17

Pravastatin

Breast cancer

NCT04385433

Ⅲ

400

40 mg·d^-1, 1 year

2020.12.4

Rosuvastatin

Breast cancer

NCT05338723

Ⅲ

20 mg·d^-1, 6 months

2020.9.15

Simvastatin

Ovarian cancer

NCT04457089

Ⅰ

40 mg·d^-1, 6 months

2021.1.25

Breast cancer

NCT03454529

Ⅱ

40 mg·d^-1, 2-4 weeks

2018.3.9

Breast cancer

NCT03971019

Ⅲ

314

20 mg·d^-1

2019.3.28

Breast cancer

NCT05550415

Ⅱ

40 mg·d^-1, 21 days

2022.8.19

Pancreatic cancer

NCT03889795

Ⅰ

5, 20, 40 mg·d^-1

2019.6.5

Hysteromyoma

NCT03400826

Ⅱ

40 mg·d^-1, 12 weeks

2018.8.20