Ferroptosis has emerged as a novel, crucial regulator of meat quality in the postmortem hypoxia environment, with its role in mediating protein oxidation and cell death. However, the interaction between ferroptosis and the hypoxia response, especially the involvement of hypoxia-inducible factor-1α (HIF-1α), remains poorly studied. This study aimed to characterize whether HIF-1α influences ferroptosis, and, if so, explore the underlying mechanisms involved. The results showed that ferroptosis mediated by HIF-1α negatively impacts meat color and water holding capacity (WHC) but improving tenderness. Inhibition of HIF-1α by 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) reduced ferroptosis, as evidenced by lower lipid ROS levels, malondialdehyde (MDA), along with higher glutathione (GSH) levels compared to the control (P < 0.05). Additionally, inhibition of HIF-1α shifted iron homeostasis towards decreased uptake via downregulation of transferrin receptor 1 (TfR1) and induced export/storage via upregulation of ferroportin (FPN) and ferritin heavy chain (FTH) (P < 0.05). The relative expression of the ferritinophagy mediator nuclear receptor coactivator 4 (NCOA4), LC3-II/LC3-I ratio, and ATG were inhibited by YC-1 (P < 0.05), these findings suggest a general decrease in ferritinophagy associated with HIF-1α inhibition. YC-1-treated samples exhibited significantly diminished lactate accumulation and lactate dehydrogenase (LDH) activity compared to the control (P < 0.05). Unexpectedly, the inhibition of ferroptosis caused by YC-1 was further amplified by lactate enhancement, suggesting that lactate can exert its suppressive effects on ferroptosis independently of HIF-1α. Collectively, these findings demonstrate that HIF-1α drives ferroptosis by regulating iron metabolism, while lactate inhibits ferroptosis in a HIF-1α-independent manner. Overall, the HIF-1α mediated ferroptosis of postmortem yak muscle had a negative impact on WHC and color, while as a contributing factor of tenderness.

2024-11-01·ANNALS OF PLASTIC SURGERY

Article

作者: Zeng, Xiuan ; Guo, Tao ; Xie, Yunfei ; Li, Meng ; Gao, Zhenyang ; Wang, Kejing ; Yang, Qibing

Background:

Hypoxia-inducible factor-1α (HIF-1α), regulated by prolyl hydroxylase, plays a central role in tissue adaptation to ischemia. This study investigates the impact of HIF-1α on angiogenesis in the Choke II zone of multiterritory perforator flaps.

Methods:

Ninety male Wistar rats were allocated into 3 groups, with 30 rats in each group: the dimethyloxalylglycine (DMOG) group, the 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1) group, and the normal saline (NS) group. All rats underwent multiterritory perforator flap surgeries on their dorsal side. Subsequently, they received intraperitoneal injections of DMOG (40 mg/kg), YC-1 (10 mg/kg), and normal saline on postoperative days 1, 2, and 3, respectively. After treatment, angiogenesis in the Choke II zone of the flap on day 7 was observed through transillumination tests and lead oxide/gelatin x-ray angiography. Histological features were determined using hematoxylin and eosin staining, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) in the Choke II region of the flap was assessed via immunohistochemistry and western blotting.

Results:

Compared to the YC-1 and NS groups, the DMOG group exhibited significant angiogenesis, resulting in a denser vascular network in the Choke II zone of the flap. The DMOG group showed significantly higher microvessel density in the Choke II zone than the YC-1 and NS groups (7.10 ± 0.99 vs 24.30 ± 3.65; 14.30 ± 2.40 vs 24.30 ± 3.65, both P<0.05). Additionally, the DMOG group demonstrated higher expression of VEGF and HIF-1α in the flaps than the other groups (P < 0.05).

Conclusions:

In summary, HIF-1α enhances the expression of VEGF, promoting angiogenesis in the Choke II zone of the multiterritory perforator flap, thus increasing the survival area.

2024-10-25·Zhen ci yan jiu = Acupuncture research

基于HIF/VEGF/Notch信号通路探讨电针“百会”“足三里”对脑缺血大鼠血管新生的影响.

Article

作者: Guan, Meng-Ya ; Wu, Song ; Ma, Su-Na ; Yang, Yue-Yue ; Wang, Jing-Ying ; Ren, Bin-Bin

OBJECTIVES:

To observe the effect of electroacupuncture (EA) on hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF)/Notch signaling pathway and related factors in rats with cerebral ischemia (CI), so as to explore its regulatory mechanism underlying improvement of CI by promoting cerebral microangiogenesis.

METHODS:

Fifteen male SD rats were randomly selected as the sham surgery (sham) group, while other 85 rats were used to prepare CI model according to the modified Zea-Longa method. The successful CI model rats (n=60) were randomly allocated to model, EA, EA+inhibitor, and inhibitor groups, with 15 rats in each group. EA stimulation (1 Hz/20 Hz, 1-2 mA) was applied to "Baihui"(GV20) and right "Zusanli"(ST36) for 30 min, once a day for 7 days. Rats of the 2 inhibitor groups received intraperitoneal injection of YC-1 (HIF-1α inhibitor, 2.5 mg/kg), once a day for 7 days. The modified neurological severity scale (mNSS, including the motor ［muscular state, abnormal movement］, sensory ［visual, tactile and proprioceptive］, balance and reflex functions, 0-18 points) was used to assess the rats' neurological deficit state. The percentage of cerebral infarct volume was measured after 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining, and pathological changes of the ischemic penumbra cortex were observed after H.E. staining. The immunoactivity of CD34 was determined using immunohistochemistry, followed by calculating the microvascular density (MVD) in the ischemic penumbra cortex, and the expression levels of HIF-1α, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), Notch1, and Delta like 4 ligand (DLL4) mRNAs and proteins in the ischemic penumbra of brain tissue were detected using real-time PCR and Western blot, respectively.

RESULTS:

In contrast to the sham group, the mNSS score, percentage of cerebral infarct volume, MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 proteins and mRNAs were all significantly increased in the model group (P<0.01). In comparison with the model group, the mNSS score and percentage of cerebral infarct volume were significantly decreased in the EA group (P<0.01), and increased in the inhibitor group (P<0.01), and the MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 proteins and mRNAs were further strikingly increased in the EA group (P<0.01), but obviously decreased in the inhibitor group (P<0.05, P<0.01). Comparison between EA and EA+inhibitor groups showed that the effects of EA were basically eliminated in lowering mNSS score and percentage of cerebral infarct volume (P<0.01), and in up-regulating MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 mRNAs and proteins (P<0.01). The levels of mNSS score and percentage of cerebral infarct volume were markedly higher (P<0.01) in the inhibitor group than those in the EA+inhibitor group, while the MVD, expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 mRNAs and proteins were significantly lower in the inhibitor group than in the EA+inhibitor group (P<0.01), suggesting an elimination of EA after administration of HIF-1α inhibitor. H.E. staining showed loosened structure and disordered arrangement of neurons, swollen and vacuolized cells with ruptured nuclei, swollen and deformed microvessels in the ischemic penumbra of the brain tissue in the model group, which was improved in the EA group, including reduction of cellular swelling degree and vacuol-like changes, relatively intact of nuclei, and increase of new capillaries.

CONCLUSIONS:

EA of GV20 and ST36 can improve neurological deficit and reduce cerebral infarct volume in CI rats, which may be associated with its functions in promoting angiogenesis in ischemic penumbra area and in up-regulating the activities of HIF/VEGF/Notch signaling pathway and related factors.

项与 YC-1 相关的新闻（医药）

2023-05-03

·医药观澜

Nature、Science子刊等发表！这7个抗肿瘤药物新靶点有何潜力？

▎药明康德内容团队编辑当下，癌症患者的治疗仍面临诸多挑战，例如：小分子药物、PD-1/L1抑制剂等靶向疗法仅对部分患者有效；CAR-T细胞治疗产品也只在血液癌症领域取得了突破；此外，癌症患者在接受已有药物治疗后，很多会不可避免地出现复发、耐药性问题等等。为此，一些科学家们正在努力寻找新的癌症治疗靶点，以期为患者带来全新的治疗选择。本文中，我们将分享2023年第一季度发表在Nature、Nature子刊及Science子刊上的7个抗肿瘤药潜在新靶点，看看它们都有望为哪类癌症患者提供新的治疗思路或方法。靶点：PI5P4Kα疾病：前列腺癌磷脂酰肌醇（PI）调节酶在癌症中经常发生改变，并已成为药物开发的重点研究对象。在2月1日发表于Science Advances上的一篇文章中，研究人员探索了磷脂酰肌醇-5-磷酸-4-激酶（PI5P4K）的功能，并证明PI5P4Kα亚型影响支持前列腺癌细胞存活的雄激素受体（AR）信号传导。研究表明，雄激素剥夺会影响磷脂酰肌醇丰度，并增强磷脂酰肌醇（4,5）二磷酸的细胞内水平，这意味着磷脂酰肌醇的调节在雄激素剥夺期间前列腺癌代谢应激适应中变得越来越重要。研究认为，PI5P4Kα-AR关系通过mTORC1失调得到缓解，并表明PI5P4Kα与溶酶体共定位，其中溶酶体是mTORC1复合物激活的细胞内位点。值得注意的是，PI5P4Kα-AR的这种关系在手术去势后的小鼠前列腺组织中变得突出。多个前列腺癌细胞模型在稳定的PI5P4Kα抑制后表现出明显的生存脆弱性。论文指出，这些结果支持将PI5P4Kα作为潜在靶标，用于解决前列腺癌日益增长的治疗抵抗性难题。靶点：PODXL疾病：前列腺癌糖萼成分和唾液粘蛋白足萼蛋白（PODXL）是一种跨膜蛋白，其升高的表达与肿瘤的不良临床结果相关，这使科学家们想到或许可以将其作为癌症转移的靶向生物标志物。鉴于PODXL在正常组织中的功能也是必需的，因此必须确定调节PODXL功能的肿瘤特异性环境。在2月3日发表于Science Advances上的一篇文章中，研究人员发现了PODXL的一项意外功能，它可作为半乳糖凝集素-3（GAL3）的诱饵受体，PODXL-GAL3相互作用释放GAL3。通过实验，研究人员确定了控制PODXL向促转移糖萼成分转变的分子机制，同时揭示了PODXL作为诱饵受体可以减轻GAL3的侵袭抑制作用，并证明这种水平的变化可用于识别具有高度转移和预后不良的前列腺癌患者。靶点：FGL2疾病：胶质母细胞瘤作为纤维蛋白原样蛋白家族的成员，纤维蛋白原样2（FGL2）在病毒感染和癌症发展中具有凝血酶原酶活性和免疫调节功能。越来越多的证据表明，FGL2通过与FcγRIIB结合并通过Th1和Th2型细胞因子调节适应性免疫，从而作为B细胞、T细胞和树突状细胞（DC）功能的免疫抑制调节剂。对癌症基因组图谱数据的分析发现，FGL2表达与GBM患者存活率呈负相关。因此，FGL2是脑肿瘤免疫治疗的一个有吸引力的靶点。在2月10日发表于Nature Communications上的一篇论文中，研究人员发现表达FGL2特异性单链可变片段（T-αFGL2）的T细胞可以诱导肿瘤特异性CD8+组织驻留记忆T（TRM）细胞，从而防止胶质母细胞瘤复发。这些CD8+TRM细胞显示出高度扩展的T细胞受体库，这与外周组织中发现的不同。当过继转移到免疫活性或T细胞缺陷的幼稚小鼠的大脑时，这些CD8+ TRM细胞会排斥神经胶质瘤细胞。从作用机制上来看，T-αFGL2细胞治疗通过CXCL9/10和CXCR3趋化因子信号增加了荷瘤小鼠中CD69+CD8+脑驻留记忆T细胞的数量。论文指出，这些发现表明肿瘤特异性脑驻留CD8+TRM细胞可能对预防脑肿瘤复发具有重要意义。靶点：SULT1A1疾病：肝癌成人肝脏恶性肿瘤包括肝内胆管癌（ICC）和肝细胞癌（HCC），是全球癌症相关死亡的第二大原因。对于晚期ICC患者，标准治疗是联合化疗。对于晚期HCC患者，标准治疗是联合免疫疗法/多激酶抑制剂。这些治疗方法虽然提高了患者的反应率和总生存率，但效果仍然不佳。在3月13日发表于Nature Cancer上的一篇文章中，通过高通量筛选、蛋白质组学和体外耐药模型，研究人员确定了小分子YC-1对来自两种肝癌类型的细胞系亚群具有选择性活性。数据证明，这种选择性是通过肝脏固有的胞质磺基转移酶SULT1A1的表达来决定的。SULT1A1使YC-1磺化，磺化刺激YC-1共价结合到蛋白靶标的赖氨酸残基上，富集RNA结合因子。通过计算分析，研究人员发现了一类更广泛的SULT1A1依赖性抗癌化合物。论文指出，这些研究表明SULT1A1有可能成为肝癌药物开发的潜在新靶点。靶点：PRRS35疾病：肝癌肝细胞主要通过分泌调节细胞增殖、新陈代谢和细胞间通讯的蛋白质发挥作用。在肝细胞癌（HCC）的进展过程中，肝细胞分泌蛋白组是动态变化的，这既是肿瘤发生的结果，也是肿瘤发生的致病因素。作为肿瘤微环境（TME）中非细胞成分的主要部分，分泌蛋白作为宿主白细胞和肿瘤细胞之间的细胞间通讯手段，其中一些可以调节TME中的中性粒细胞行为。在3月18日发表于Nature Communications的一篇文章中，研究人员通过对肝细胞和肝癌细胞系的分泌蛋白组分析发现，蛋白酶PRSS35在HCC中起肿瘤抑制因子作用。研究显示，活性PRSS35是通过前蛋白转化酶的切割进行加工的，而后活性PRSS35通过靶向切割串联赖氨酸（KK）的特定区域来抑制CXCL2的蛋白质水平。CXCL2的降解减弱了中性粒细胞向肿瘤的募集和中性粒细胞胞外陷阱的形成，最终抑制了HCC进展。论文指出，这些发现扩展了我们对肝细胞分泌蛋白组在癌症发展中的作用的理解，同时为PRRS35作为治疗靶点或诊断生物标志物的临床转化提供了基础。靶点：RBFOX2疾病：胰腺癌胰腺导管腺癌（PDAC）极具侵略性，且转移性强，对于造成PDAC转移的驱动基因突变目前仍是未知。今年3月22日发表在Nature期刊的一篇文章中，研究人员分析了大量原发性和转移性PDAC肿瘤的RNA剪接数据，以识别与PDAC进展相关的差异性剪接事件。数据显示：在患者来源的异种移植（PDX）转移性PDAC细胞系中，过表达RBFOX2会显著降低这些细胞的体外和体内转移能力；而在原发性胰腺肿瘤细胞系中，RBFOX2的耗竭则增加了这些细胞的转移潜力。这些发现显示RBFOX2可能具潜在抑制PDAC转移的作用。RNA测序和剪接进一步分析发现，RBFOX2剪接活性在细胞骨架的组织和成纤维连接的形成中发挥作用。其中，RBFOX2调控的肌球蛋白磷酸酶RHO相互作用蛋白（MPRIP）剪接，被证实与PDAC的转移、细胞骨架组织的改变和成纤维连接的诱导相关联。论文指出，通过对RBFOX2选择性剪接事件的精确调节可能作为PDAC的潜在治疗方式。靶点：TRABID疾病：前列腺癌双链断裂(DSB)对基因组稳定性构成重大威胁，并与染色体易位和癌症有关。双链断裂主要通过同源重组和非同源末端连接进行修复。DNA损伤反应(DDR)蛋白p53结合蛋白1（53BP1）在维持同源重组和非同源末端连接之间的平衡中起着重要作用。而泛素化在调节53BP1 DNA双链断裂的解离中扮演着重要的角色。然而，对于这个过程是如何被调控的我们仍然知之甚少。在3月31日发表于Nature Communications上的一篇文章中，研究人员证明了 TRABID去泛素化酶在内源性水平与53BP1结合，并在双链断裂位点调节53BP1的保留。TRABID去泛素化由E3泛素连接酶SPOP介导的53BP1的K29连接多聚泛素化，并阻止53BP1从双链断裂中解离，从而诱导同源重组缺陷和染色体不稳定。具有TRABID过表达的前列腺癌细胞对PARP抑制剂表现出高度敏感性。论文指出，该研究工作表明TRABID通过在双链断裂位点诱导延长的53BP1保留，促进DNA修复期间的非同源末端连接修复而不是同源重组，这表明TRABID过表达可以预测同源重组缺陷和PARP抑制剂在前列腺癌中的潜在治疗用途。参考资料（可上下滑动查看） [1] RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer. Retrieved Mar 22, 2023, from https://www.nature.com/articles/s41586-023-05820-3[2] SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers. Retrieved Mar 13, 2023, from https://www.nature.com/articles/s43018-023-00523-0[3]Secreted protease PRSS35 suppresses the hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps. Retrieved Mar 18, 2023, from https://www.nature.com/articles/s41467-023-37227-z[4]Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Retrieved Feb 03, 2023, from https://www.science.org/doi/10.1126/sciadv.abq1858[5]PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition. Retrieved Feb 01, 2023, from https://www.science.org/doi/10.1126/sciadv.ade8641[6]TRABID overexpression enables synthetic lethality to parp inhibitor via prolonging 53BP1 retention at double-strand breaks. Retrieved Mar 31, 2023, from https://www.nature.com/articles/s41467-023-37499-5[7]FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain resident memory T cells. Retrieved Feb 10, 2023, from https://www.nature.com/articles/s41467-023-36430-2本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

细胞疗法免疫疗法

2023-03-31

·生物谷

Nat Cancer：科学家有望开发出一种治疗肝癌的新疗法

来自美国国立卫生研究院等机构的科学家们通过研究解开了一种能抵御人类肝癌的潜在新型策略，其或有望帮助研究人员开发新型的抗癌药物。包括肝脏内胆管癌和肝细胞癌在内的成人肝脏恶性肿瘤是全球癌症相关死亡的第二大原因,大部分的患者都会接受化疗或免疫疗法，或者两种疗法的组合，同时也并没有特定的生物标志物可以选择。近日，一篇发表在国际杂志Nature Cancer上题为“SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers”的研究报告中，来自美国国立卫生研究院等机构的科学家们通过研究解开了一种能抵御人类肝癌的潜在新型策略，其或有望帮助研究人员开发新型的抗癌药物；通过对细胞和小鼠进行一系列实验，研究人员发现，肝癌细胞中所产生的特殊酶类或能将一类化合物转化为抗癌药物，并能杀灭动物机体的癌细胞以及减轻疾病程度。研究人员建议，这种酶类或能成为一种潜在的靶点来帮助开发抵御肝癌或其它类型癌症的新型药物。Matthew Hall博士说道，我们发现了一种特殊分子，其能以一种特殊的方式来杀灭罕见的肝癌细胞，这种分子是我们在筛选能选择性杀灭人类肝癌细胞的化合物分子中筛选出来的，我们花费了大量工作才发现它，而且其能在这些肝癌细胞中被一种酶类进行转化，并产生一种毒性的抗癌药物。研究者Bardeesy最初对人类胆管癌进行研究，其是一类影响机体胆管的肝癌，主要特征表现为IDH1酶类的突变，于是研究者就想通过研究来发现特殊化合物和药物来有效抵御IDH1的突变，通过进行大量联合研究，研究人员就能快速检测数千种已经获批的药物和实验性抗癌制剂在以IDH1为靶点的情况下杀灭胆管癌细胞的作用效果。于是研究人员发现了多种分子（其中包括YC-1）能杀灭癌细胞，然而，当他们想观察YC-1是如何发挥作用时，他们发现这种化合物或许并不能影响IDH1的突变。研究人员表示，肝癌细胞能产生一种名为SULT1A1的酶类，该酶能激活YC-1化合物，从而使其对癌细胞培养物和肝癌小鼠模型机体中的肿瘤具有一定的毒性，在利用YC-1治疗的动物模型中，肝脏肿瘤要么生长会减速要么就会发生萎缩，相反，研究人员在携带缺失该酶的癌细胞的动物模型中并未发现利用YC-1治疗后肿瘤发生任何变化。于是研究人员分析了化合物和药物文库中的其它药物筛选结果的数据库，从而将药物的活性与SULT1A1的活性进行匹配，他们还查看了美国国家癌症研究所的一个大型的抗癌化合物数据库，从而来测试其对该酶类活性的其它可能性。科学家有望开发出一种治疗肝癌的新疗法。图片来源：Nature Cancer (2023). DOI:10.1038/s43018-023-00523-0 随后研究人员识别出了多种依赖SULT1A1的化合物或许具有一定的杀灭肿瘤的活性，利用计算方法，研究者也预测了其它依赖于SULT1A1的化合物；研究者Hall说道，一旦我们发现SULT1A1能激活YC-1，或许还会陆续出现其它问题，比如还有哪些化合物具有活性并能通过同样的机制来杀灭细胞？我们能否识别出正在开发的其它化合物并阐明其也因SULT1A1的激活而具有一定的活性？答案是肯定的，而且研究人员也发现了与YC-1具有相同作用机制的其它化合物。研究人员认为这些研究发现对于开发新型抗癌药物具有广泛的意义，这些分子或许有望作为一类未被开发的抗癌药物，其依赖于SULT1A1的活性来抵御肿瘤。研究人员还将YC-1和相似的分子视为能开发对细胞上的重要蛋白质非常有效的化合物的原型，通过修饰这些分子的不同部位或许就能使其对于这种蛋白质更加具有针对性，而创建SULT1A1激活分子的工具包或许会影响很多不同的作用靶点。而诸如这样一个工具包会由数百个已知的分子组成，从理论上来讲，这种工具包会涵盖多种类型的酶类，即硫酸基转移酶（sulfotransferases），其能在机体的不同组织中处于活性；比如，除了SULT1A1外，人类的硫酸基转移酶也会在大脑中处于活跃状态，其能激活工具包中的一个分子子集，这对于开发对脑癌非常特殊的药物非常有用。研究者表示，我们知道SULT1A1依赖性的药物已经被发现，而本文研究结果也表明，或许还存在其它SULT1A1依赖性的化合物会携带一系列不同的靶点；而识别诸如此类化合物和细胞上的靶点对于开发其它类型的小分子和药物具有非常重要的意义，这并不仅仅是针对一部分癌症类型，而且其有望成为一种治疗其它疾病的新方法。综上，本文研究结果为进行这些制剂的临床前开发奠定了基础，同时研究者指出了利用SULT1A1活性来开发选择性靶向性策略的广泛潜力。（生物谷Bioon.com）原始出处： Lei Shi，William Shen,Mindy I. Davis, et al. SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers, Nature Cancer (2023). DOI:10.1038/s43018-023-00523-0

免疫疗法

2023-03-14

·World Pharma News

Scientists reveal a potential new approach to treating liver cancer

Scientists at the National Institutes of Health and Massachusetts General Hospital in Boston have uncovered a potential new approach against liver cancer that could lead to the development of a new class of anticancer drugs. In a series of experiments in cells and mice, researchers found that an enzyme produced in liver cancer cells could convert a group of compounds into anticancer drugs, killing cells and reducing disease in animals. The researchers suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps other cancers and diseases as well. "We found a molecule that kills cells in a rare liver cancer in a unique way," said translational scientist Matthew Hall, Ph.D., one of the leaders of the work at NIH's National Center for Advancing Translational Sciences (NCATS). "It emerged from a screening to find molecules that selectively kill human liver cancer cells. It took a lot of work to figure out that the molecule is converted by an enzyme in these liver cancer cells, creating a toxic, anticancer drug." Hall, Nabeel Bardeesy, Ph.D., a liver cancer specialist at Massachusetts General Hospital and their colleagues reported their results March 13 in Nature Cancer. The finding stems from a collaboration between Massachusetts General Hospital and NCATS researchers. Bardeesy was originally studying cholangiocarcinoma, a type of liver cancer that affects the bile duct. The cancer is characterized by mutations in the IDH1 enzyme. Bardeesy's team wanted to find compounds and drugs that might be effective against the IDH1 mutation. Through a collaboration with NCATS, Hall and other NCATS scientists rapidly tested thousands of approved drugs and experimental cancer agents for their effectiveness in killing cholangiocarcinoma cells, with IDH1 as a target. They found several molecules, including one called YC-1, could kill the cancer cells. Yet, when they looked to see how YC-1 was working, they discovered the compound wasn't affecting the IDH1 mutation. The Massachusetts researchers showed that the liver cancer cells made an enzyme, SULT1A1. The enzyme activated the YC-1 compound, making it toxic to tumor cells in cancer cell cultures and mouse models of liver cancers. In the animal models treated with YC-1, the liver tumors either had reduced growth or shrank. Conversely, the researchers found no changes in tumors treated with YC-1 in animals with cancer cells lacking the enzyme. The researchers examined other databases of drug screening results in compound and drug libraries to match drug activity with SULT1A1 activity. They also looked at a large National Cancer Institute database of anticancer compounds for additional possibilities to test for their activity with the enzyme. They identified several classes of compounds that relied on SULT1A1 for their tumor-killing activity. Using computational methods, they predicted other compounds that also likely were dependent on SULT1A1. "Once we found SULT1A1 activated YC-1, it led us to ask, 'What other compounds are active and can kill cells by the same mechanism?'" Hall said. "Can we identify other compounds that were being developed and demonstrate that they were also active because of SULT1A1 activation? The answer was yes. We found other compounds with the same mechanism of action as YC-1." The scientists suggest these findings have broader implications for developing new anticancer drugs. "We think these molecules have the potential to be an untapped class of anticancer drugs that depend on SULT1A1 for their activity against tumors," Bardeesy said. The researchers see YC-1 and similar molecules as prototypes for developing compounds that could be effective against important proteins on cells. Modifying different parts of these molecules could make them more specific for such proteins. The researchers point to the creation of a "toolkit of SULT1A1-activated molecules" that could affect many different targets. Such a toolkit is comprised of hundreds of known molecules. In theory, the toolkit covers many types of enzymes, called sulfotransferases, that are active in different tissues in the body. For example, in addition to SULT1A1, the human sulfotransferase SULT4A1 is active in the brain. It can activate a subset of the molecules in the toolkit. This might be useful in developing drugs specific for brain cancers. "We knew SULT1A1-dependent drugs had already been identified," Bardeesy said. "Our results suggest there could be other SULT1A1-dependent compounds with ranges of different targets. Identifying such compounds and targets on cells could have potential implications for developing other types of small molecules and drugs, not just limited to these cancers. This might become a new approach for some diseases." This work was supported by the MGH Fund for Medical Discovery Award; the Cholangiocarcinoma Foundation Christopher J. Wilke Memorial Research Fellowship; NCI 1K99CA245194-01, the V Foundation for Cancer Research, the Department of Defense Translational Team Science Award W81XWH-17-1-0491; NCI SPORE P50 CA127003; the Gallagher Chair in Gastrointestinal Cancer Research and Target Cancer Foundation; and the MGH Excellence Award. Shi L, Shen W, Davis MI, Kong K, Vu P, Saha SK, Adil R, Kreuzer J, Egan R, Lee TD, Greninger P, Shrimp JH, Zhao W, Wei TY, Zhou M, Eccleston J, Sussman J, Manocha U, Weerasekara V, Kondo H, Vijay V, Wu MJ, Kearney SE, Ho J, McClanaghan J, Murchie E, Crowther GS, Patnaik S, Boxer MB, Shen M, Ting DT, Kim WY, Stanger BZ, Deshpande V, Ferrone CR, Benes CH, Haas W, Hall MD, Bardeesy N. SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers. Nat Cancer. 2023 Mar 13. doi: 10.1038/s43018-023-00523-0

100 项与 YC-1 相关的药物交易

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