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Volume 41 Issue 4
Apr.  2023
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WEN Ping, ZHANG Junping. Progress on the antitumor activity of cryptotanshinone and its derivatives[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(4): 207-211. doi: 10.12206/j.issn.2097-2024.202208090
Citation: WEN Ping, ZHANG Junping. Progress on the antitumor activity of cryptotanshinone and its derivatives[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(4): 207-211. doi: 10.12206/j.issn.2097-2024.202208090

Progress on the antitumor activity of cryptotanshinone and its derivatives

doi: 10.12206/j.issn.2097-2024.202208090
  • Received Date: 2022-08-22
  • Rev Recd Date: 2023-03-15
  • Publish Date: 2023-04-25
  • Cryptotanshinone is one of the effective components of traditional Chinese medicine salvia miltiorrhiza which shows good activities against a variety of tumors. Its anti-tumor effects include inhibition of tumor cell proliferation, induction of cell apoptosis, inhibition of cell migration and invasion, regulation of immune function and reversal of drug resistance. The direct anti-tumor targets include signal transducer and activator of transcription 3 (STAT3), tyrosine protein phosphatase SHP2, DNA topoisomerase 2, and other mechanisms of action include the induction of reactive oxygen species (ROS) production, regulation of estrogen and androgen receptor signaling, and inhibition of PI3K/AKT signaling pathway. In addition, many cryptotanshinone derivatives have been designed and synthesized to study the antitumor effects. The research progress of the antitumor activity of cryptotanshinone and its derivatives were reviewed in this paper to give references to the anti-tumor drug development of cryptotanshinone and its derivatives.
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Progress on the antitumor activity of cryptotanshinone and its derivatives

doi: 10.12206/j.issn.2097-2024.202208090

Abstract: Cryptotanshinone is one of the effective components of traditional Chinese medicine salvia miltiorrhiza which shows good activities against a variety of tumors. Its anti-tumor effects include inhibition of tumor cell proliferation, induction of cell apoptosis, inhibition of cell migration and invasion, regulation of immune function and reversal of drug resistance. The direct anti-tumor targets include signal transducer and activator of transcription 3 (STAT3), tyrosine protein phosphatase SHP2, DNA topoisomerase 2, and other mechanisms of action include the induction of reactive oxygen species (ROS) production, regulation of estrogen and androgen receptor signaling, and inhibition of PI3K/AKT signaling pathway. In addition, many cryptotanshinone derivatives have been designed and synthesized to study the antitumor effects. The research progress of the antitumor activity of cryptotanshinone and its derivatives were reviewed in this paper to give references to the anti-tumor drug development of cryptotanshinone and its derivatives.

WEN Ping, ZHANG Junping. Progress on the antitumor activity of cryptotanshinone and its derivatives[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(4): 207-211. doi: 10.12206/j.issn.2097-2024.202208090
Citation: WEN Ping, ZHANG Junping. Progress on the antitumor activity of cryptotanshinone and its derivatives[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(4): 207-211. doi: 10.12206/j.issn.2097-2024.202208090
  • 隐丹参酮(CTS)是中药丹参的有效成分之一,国内外研究证明CTS具有抗肿瘤、抗炎、神经保护、心血管保护、抗纤维化和调节代谢紊乱等药理特性,具有广阔的临床应用前景。抗肿瘤作用是近年来隐丹参酮药理活性研究的热点问题之一[1]。隐丹参酮对肺癌、肝胆癌、胃癌、食管癌、乳腺癌、前列腺癌、胰腺癌、结直肠癌、骨肉瘤癌、黑色素瘤、横纹肌瘤、食管鳞状癌等多种恶性肿瘤表现出一定的抑制活性,其抗肿瘤机理包括抑制肿瘤细胞增殖、迁移和侵袭,诱导细胞凋亡,调节免疫以及抑制包括STAT3在内的多种信号通路[2-4]。由于CTS中等强度的药理活性和选择性,近年来研究人员对CTS进行了大量结构修饰,期望获得靶点明确且药理活性更强的CTS衍生物,从而开发并应用于临床治疗。本文就隐丹参酮及其衍生物在抗肿瘤方面的作用及其机制进行综述。

    • 癌细胞的主要特点是具有无限的增殖能力。研究表明,CTS可以抑制多种肿瘤细胞增殖,包括胰腺癌细胞BxPC-3、慢性髓性白血病细胞K562/ADR、胶质瘤细胞U87、人卵巢癌细胞Hey、前列腺癌细胞DU145、乳腺癌细胞MCF7、食管鳞状细胞癌ESCC等[5]

    • 细胞凋亡又称细胞程序性死亡,对于维持组织稳态和消除不需要或受损细胞起重要作用。研究发现,CTS可以诱导多种肿瘤细胞凋亡,包括骨髓瘤细胞U266、人结肠癌细胞系SW620 Ad300和HCT116、人胃癌细胞MKN-45、肝癌细胞Hepa1-6、非小细胞肺癌细胞A549 和H460 、黑色素瘤细胞A375、横纹肌肉瘤细胞Rh30等[6]

    • 高侵袭性和转移是癌细胞恶性特征,转移是癌症死亡的主要原因。因此,抑制癌细胞转移能有效降低癌症死亡率。研究发现,CTS能够抑制卵巢癌细胞A2780的迁移和侵袭[7]。此外,CTS还可以抑制食管癌细胞EC109、膀胱癌细胞T24、人舌鳞癌细胞CAL27、小鼠结肠癌细胞CT26等多种肿瘤细胞的迁移和侵袭[5]

    • 隐丹参酮不仅能够直接抑制多种肿瘤细胞的生长,还可以诱导机体产生抗肿瘤免疫反应,从而间接发挥抗肿瘤效应。研究发现,隐丹参酮能够通过增加CD4+T细胞的细胞毒作用,抑制人非小细胞肺癌H446细胞和乳腺癌MCF7细胞的生长[8]。此外,隐丹参酮还可以通过诱导小鼠树突状细胞成熟,促进抗原提呈功能,进而诱导T细胞活化增殖,抑制Lewis肺癌细胞的增殖[9]。肿瘤相关巨噬细胞 (TAM) 是肿瘤组织中浸润的巨噬细胞,具有异质性,可分为M1和M2表型。M2表型的TAM能够促进肿瘤生长和转移,相反,M1表型则具有肿瘤抑制和促炎特性。研究发现,隐丹参酮和PD-L1联合治疗能够诱导巨噬细胞向M1极化,从而抑制小鼠肝癌Hepa1-6移植瘤的生长[10]

    • 耐药是导致肿瘤复发和治疗失败的主要原因。研究表明,CTS能够逆转慢性骨髓性白血病细胞K562对伊马替尼的耐药性[11],改善A549细胞对顺铂的耐药性[12]。此外,CTS还可以逆转P-糖蛋白(p-gp)过表达的结肠癌细胞SW620 Ad300对多柔比星和伊立替康的多重耐药[13]

    • 除了具有以上活性之外,CTS还可以与其他不同抗癌药物或细胞因子协同发挥抗肿瘤作用。例如,CTS和紫杉醇的联合用药比单独用药更能有效诱导舌鳞状细胞癌CAL27和SCC-9细胞的凋亡[14]。新近研究发现,CTS与小剂量的抗PD-L1抗体合用对小鼠Lewis 肺癌的生长抑制作用明显优于CTS单独应用[9]

    • 自噬,即Ⅱ型程序性细胞死亡,作为凋亡之外的另一种可以杀死细胞的途径,是一种抑制癌细胞生长的新方法。研究显示,CTS可通过诱导结肠癌SW620 Ad300细胞和A549细胞自噬促进细胞死亡[15-16]

    • CTS抑制肿瘤细胞增殖、迁移和侵袭,诱导细胞凋亡,以及调节免疫等作用的机制十分广泛,涉及靶点STAT3、酪氨酸蛋白磷酸酶SHP2、DNA拓扑异构酶和信号通路磷酸酰肌醇3-激酶(PI3K)/丝氨酸/苏氨酸激酶Akt等。

    • STAT3由Janus激酶(JAKs)激活,参与肿瘤增殖、凋亡、血管生成及免疫逃逸等。STAT3在大多数恶性肿瘤中被组成性激活,异常的STAT3信号传导是肿瘤恶性进展的重要过程。当705位酪氨酸残基磷酸化后,STAT3被激活,单体STAT3通过其SH2结构域形成二聚体,并从细胞质转移到细胞核中,调节其靶基因的表达,例如,上调cyclin D1、survivin、Mcl-1、MYC、BCL-XL表达,下调 p53表达,促进肿瘤细胞增殖和存活;上调MMP2/9、Twist1、Vimentin表达,促进肿瘤转移;上调TGF-β、IL-6/10、PD-1、PD-L1、VEGF表达,下调CD80/86、MHCII、TNF、IL-12、CCL5、CXCL10等表达,抑制肿瘤微环境免疫功能[17]。研究发现,CTS能够直接与STAT3的SH2结构域结合,特异性抑制STAT3 Tyr705的磷酸化,抑制STAT3二聚化[18-19],相比之下,姜黄素还能抑制Jak2的表达[20]。在人胰腺癌BxPC-3细胞中,CTS能够抑制BxPC-3细胞的STAT3信号通路进而抑制细胞增殖,诱导细胞凋亡,达到抗肿瘤的作用[21]。另外,CTS作为p-STAT3抑制剂,能够有效阻断IL-6介导的STAT3活化,抑制肿瘤增殖,逆转BCR-ABL激酶非依赖性耐药途径[11]。此外,CTS和紫杉醇联合治疗能够有效地抑制舌鳞状癌TSCC细胞增殖和迁移,其作用机制同样与抑制STAT3信号通路相关[14]。沉默信息转录调控因子3(SIRT3)是一种蛋白质去乙酰化酶,参与癌症、心血管、神经系统等疾病的发展过程。研究发现CTS能够通过抑制STAT3/SIRT3 信号通路抑制人卵巢癌A2780 细胞增殖[22]。 上述研究表明,抑制STAT3信号通路对于CTS抗肿瘤至关重要,且CTS是一种特异性的STAT3抑制剂。

    • 含Src同源2结构域蛋白酪氨酸磷酸酶(SHP2)由基因PTPN11编码,PTPN11突变引起SHP2催化活性异常增加。研究发现,肺癌、结肠癌、黑色素瘤、神经母细胞瘤、肝癌和急性髓性白血病等病人均发现有PTPN11突变[23]。SHP2是一种非受体蛋白酪氨酸磷酸酶,参与Ras-Erk、PI3K-Akt、Jak-Stat和NF-κB多条信号通路传导,调控细胞的增殖、迁移和凋亡等过程[24]。研究证明,CTS能与SHP2直接结合,是一个混合型蛋白酪氨酸磷酸酶抑制剂,抑制SHP2 的IC50为22.50μmol/L,抑制SHP1的IC50为39.50μmol/L。用SHP2 siRNA敲减Hela细胞中SHP2后,CTS抑制Hela细胞生长的敏感性降低,提示SHP2是CTS的一个靶点,但是,CTS仍然可以进一步抑制SHP2敲减细胞生长,说明CTS还有其它作用靶点[25]。此外,有研究发现,CTS能够上调胶质瘤细胞 U87 SHP2蛋白酪氨酸磷酸酶活性,抑制STAT3 Tyr705的磷酸化,从而在体内外表现出抑制恶性胶质瘤活性[26]

    • DNA拓扑异构酶 (topos),包括DNA拓扑异构酶1(topo1)和DNA拓扑异构酶2(topo2),其中topo2因其在有丝分裂中的关键作用被认为是抗癌治疗的重要靶点[27]。研究表明,CTS能够显著降低前列腺癌PC3细胞中topo 2a的mRNA、蛋白和酶活性水平,并且在裸鼠异种移植模型中表现出良好的抗肿瘤作用[28]

    • 活性氧与肿瘤的发展密切相关,其过度产生可诱导多种生物学效应,包括抑制细胞增殖、诱导细胞凋亡和自噬等[29]。研究发现,CTS能够促进胃癌MKN-28 细胞ROS的累积,通过调控MAPK和AKT信号通路诱导G2/M周期阻滞[30];通过ROS-线粒体途径,上调cleaved caspases-3、促凋亡蛋白Bax和下调抗凋亡蛋白Bcl-2,从而诱导黑色素瘤细胞凋亡[31];诱导横纹肌肉瘤Rh30细胞ROS产生,激活JNK/p-38,抑制Erk1/2,导致细胞凋亡[32];刺激SW620 Ad300细胞中的ROS产生,诱导p38 MAPK激活,导致NF-κB从细胞质转移到细胞核中,最终导致自噬发生[15];刺激HepG2和MCF-7细胞产生ROS,激活内质网(ER)应激,增强不同抗癌药物或细胞因子(Fas/Apo-1、TNF-α、顺铂、依托泊苷或5-FU)诱导的细胞凋亡[33]

    • 雄激素受体(AR)和雌激素受体(ER)分别是治疗前列腺癌PCa和乳腺癌的主要靶点。研究发现CTS可以通过抑制AR二聚化有效抑制AR活性,从而抑制AR+ PCa细胞的生长[34];在异种移植动物模型中,CTS可以有效抑制人前列腺癌CWR22Rv1细胞的生长和AR靶基因的表达[35]。此外,CTS还能够抑制乳腺癌细胞的生长,通过竞争性地结合ERα抑制E2诱导的ER转录活性和ER靶基因的表达[36];同时,CTS可以有效地抑制体内异种移植瘤模型中ER信号,发挥抗肿瘤作用[37]

    • 磷酸肌醇3-激酶(PI3K)/蛋白质丝氨酸苏氨酸激酶(Akt)信号通路参与肿瘤的发生、生长、存活和转移。有研究发现CTS可抑制PI3K/AKT信号通路,增加caspase-3、caspase-9、PARP和Bax的表达,降低Bcl-2、survivin、细胞凋亡抑制蛋白的表达,诱导非小细胞肺癌细胞的凋亡[38-39]。酪氨酸激酶胰岛素生长因子1受体(IGF-1R)在肿瘤细胞的生长、分化和进展中起关键的作用。研究表明,CTS能够通过下调IGF-1R/PI3K/Akt信号通路抑制人肺癌细胞的增殖[40]。此外,有文献报导CTS可以通过调节PI3K/Akt/mTOR信号,抑制结肠癌CT26细胞的侵袭[41]。在裸鼠异种移植实验中,CTS能够显著抑制小鼠体内异种移植物的生长,其作用机制与抑制PI3K/AKT/NF-κB信号通路有关[42]。以上研究表明PI3K/AKT信号通路可能是CTS抗肿瘤的有效信号通路之一。

    • CTS虽然具有广谱的抗肿瘤活性,但是其药理作用中等,疏水性强且难吸收,口服生物利用度只有2.1%,这些缺点严重阻碍了其开发和应用[43]。近年来,针对CTS存在的问题,人们尝试对CTS进行结构改造,期望获得生物活性高、水溶性好的化合物。刘航[44]等基于CTS是一种STAT3抑制剂,通过对CTS及其骨架类似物进行修饰,设计合成了CTS衍生物62个,其中新化合物46个,通过报告基因法检测发现有27个新化合物对STAT3转录抑制效果优于CTS,IC50最低0.5976 μmol/L。Wang等基于STAT3的药物设计策略,设计合成了一种亲和力和抑制活性更强的新型CTS衍生物LYW-6,该化合物与STAT3结合解离常数Kd约为6.6μmol/L,能够显著抑制STAT3磷酸化、二聚化、核转位以及转录活性。在细胞水平上,LYW-6能选择性抑制高STAT3活性的结肠癌细胞增殖、迁移,促进凋亡,体内可抑制结肠癌的生长和转移,是一个具有开发前景的抗肿瘤活性化合物[45]。为了改善CTS的水溶性,Xu等合成了几种CTS的钠盐衍生物,结果发现这些衍生物比CTS更易溶解,同时保留了CTS的生物活性,其中钠盐衍生物PTS33可以有效地抑制二氢睾酮DHT诱导AR反式激活和PCa细胞生长[46]

    • CTS具有广谱的抗肿瘤活性,该活性与抑制肿瘤细胞增殖、迁移和侵袭,诱导细胞凋亡,逆转耐药性,诱导自噬等作用相关。除直接作用于肿瘤细胞外,CTS还可以通过增强CD4+T细胞的细胞毒作用、诱导DC细胞成熟和促使巨噬细胞M1型极化,间接杀伤肿瘤细胞。分子机制研究表明,CTS可直接结合STAT3和SHP2,有效调节JAK/STAT3、NF-κB、PI3K/AKT和IGF-1R等信号通路发挥抗肿瘤作用。隐丹参酮特异性抑制STAT3信号通路,而不抑制STAT家族中的其他蛋白,是其一大特点。因为尽管其他天然产物也有抗肿瘤作用,但不是特异性STAT3抑制剂,例如姜黄素,是一种STAT抑制剂,但在治疗24 h后降低了STAT3的表达。虽然CTS表现出良好的药理活性,但水溶性差和生物利用度低等问题限制了其广泛应用。因此,基于靶点STAT3,以CTS作为先导化合物,设计并合成一系列CTS衍生物,有望开发出新型STAT3抑制剂用于癌症治疗。

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