Brequinar Sodium

虽然化疗成功地治疗了癌症并延长了许多患者的生命，但它并不总是对每个人都有效。癌细胞会重新调整它们将燃料转化为能量的代谢过程，以规避化疗药物的作用。许多化疗药物都是所谓的抗代谢药，旨在破坏肿瘤生长和存活所需的细胞过程。 前不久，来自纽约大学、劳拉和艾萨克-珀尔穆特癌症中心以及马萨诸塞大学的研究人员揭示了癌细胞逃避化疗药物的两种方式。相关研究结果于2024年11月26日在线发表在Nature Metabolism期刊上，论文标题为“Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition”。 化疗药物与嘧啶合成 在这项研究中，研究人员使用了三种化疗药物：雷替曲塞（raltitrexed）、N-（膦酰乙酰）-L-天冬氨酸（PALA）和布喹那（brequinar）。这些药物能够阻止癌细胞制造嘧啶，而嘧啶是构成RNA和DNA的重要组成部分。癌细胞必须获得足够的嘧啶才能快速增殖和生长。某些化疗药物通过破坏嘧啶合成途径，使癌细胞迅速陷入饥饿状态，并最终导致细胞凋亡（apoptosis，即程序性细胞死亡）。 低糖环境下的生存策略 然而，癌细胞并不会轻易放弃。研究人员发现，在葡萄糖（血糖的化学术语）供应不足的情况下，癌细胞仍然能够找到生存的方法。这种低糖环境实际上减缓了尿苷核苷酸（uridine nucleotides）的消耗，从而降低了化疗药物的效果。正常情况下，尿苷核苷酸的制造和消耗是为了帮助构建遗传密码和促进细胞代谢。但当化疗药物阻断了DNA和RNA的合成时，尿苷核苷酸库的消耗也被阻断了，因为需要葡萄糖将尿苷的一种形式UTP转变成另一种可用的形式UDP-葡萄糖。 图：葡萄糖将UTP分流到UDP-葡萄糖合成途径，在抑制 DHODH 时会增加复制压力 低糖环境的影响 具有讽刺意味的是，低葡萄糖的肿瘤微环境反而减缓了细胞对尿苷核苷酸的消耗，从而可能减缓了癌细胞的死亡率。癌细胞需要耗尽包括尿苷核苷酸在内的嘧啶构成单元，然后才会自我毁灭。此外，低糖环境还无法激活位于线粒体表面的两种蛋白——BAX和BAK。这些蛋白被激活后会瓦解线粒体，并立即引发一系列有助于启动细胞凋亡的Caspase酶。 研究的意义 论文第一作者、纽约大学格罗斯曼医学院病理学系博士后研究员Minwoo Nam博士说：“我们的研究显示了癌细胞如何抵消低葡萄糖肿瘤微环境的影响，以及这些代谢变化如何最大限度地降低化疗药物的效果。我们的研究结果解释了肿瘤微环境中的代谢改变如何影响化疗的问题：低血糖减缓了尿苷核苷酸的消耗和耗竭，而这是促进癌细胞生长并阻碍其凋亡所必需的。” Possemato教授指出，未来可以利用这些研究成果开发新的化疗或联合疗法，以改变癌细胞在低糖微环境中的反应，使其与在其他稳定葡萄糖微环境中的反应相同。此外，还可以开发诊断测试来测量患者的癌细胞如何最有可能对低血糖微环境产生反应，并预测患者对特定化疗药物的反应程度。 未来的方向 Possemato团队计划进一步研究阻断其他癌细胞通路如何触发细胞凋亡以应对这类化疗药物。他提到，一些实验性药物，如Chk-1抑制剂和ATR抑制剂，已经可以达到这一目的，但由于患者对这些药物的耐受性不佳，还需要研究更多的药物。 在这项研究中，研究人员扫描了已知参与细胞代谢的3000个癌细胞基因，通过基因缺失确定哪些基因是癌细胞在化疗后存活所必需的。他们发现，大多数对细胞在低糖肿瘤环境中存活至关重要的基因也参与了嘧啶合成，这是许多化疗药物所靶向的一个精确生物途径。因此，他们的实验重点是研究不同实验室培养的克隆癌细胞在化疗后对低葡萄糖的反应，以及糖含量降低会影响哪些其他化学过程。 参考资料： Minwoo Nam et al. Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition. Nature Metabolism, 2024, doi:10.1038/s42255-024-01166-w. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

Laboratory experiments with cancer cells reveal two ways in which tumors evade drugs designed to starve and kill them, a new study shows. NEW YORK, Nov. 26, 2024 /PRNewswire/ -- While chemotherapies successfully treat cancers and extend patients' lives, they are known not to work for everyone for long, as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs' effects. Many of these drugs are so-called antimetabolics, disrupting cell processes needed for tumor growth and survival. Three such drugs used in the study — raltitrexed, N-(phosphonacetyl)-l-aspartate (PALA), and brequinar — work to prevent cancer cells from making pyrimidines, molecules that are an essential component to genetic letter codes, or nucleotides, that make up RNA and DNA. Cancer cells must have access to pyrimidine supplies to produce more cancer cells and to produce uridine nucleotides, a primary fuel source for cancer cells as they rapidly reproduce, grow, and die. Disrupting the fast-paced but fragile pyrimidine synthesis pathways, as some chemotherapies are designed to do, can rapidly starve cancer cells and spontaneously lead to them dying (apoptosis). Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the new study shows how cancer cells survive in an environment made hostile by the persistent shortage of the energy from glucose (the chemical term for blood sugar) needed to drive tumor growth. This better understanding of how cancer cells evade the drugs' attempts to kill them in a low-glucose environment, the researchers say, could lead to the design of better or more effective combination therapies. Publishing in the journal Nature Metabolism online Nov. 26, study results showed that the low-glucose environment inhabited by cancer cells, or tumor microenvironment, stalls cancer cell consumption of existing uridine nucleotide stores, making the chemotherapies less effective. Normally, uridine nucleotides would be made and consumed to help make the genetic letter codes and fuel cell metabolism. But when DNA and RNA construction is blocked by these chemotherapies, so too is the consumption of uridine nucleotide pools, the researchers found, as glucose is needed to change one form of uridine, UTP, into another usable form, UDP-glucose. The irony, researchers say, is that a low-glucose tumor microenvironment is in turn slowing down cellular consumption of uridine nucleotides and presumably slowing down rates of cell death. Researchers say cancer cells need to run out of pyrimidine building blocks, including uridine nucleotides, before the cells will self-destruct. In other experiments, low-glucose tumor microenvironments were also unable to activate two proteins, BAX and BAK, sitting on the surface of mitochondria, a cell's fuel generator. Activation of these trigger proteins disintegrates the mitochondria, and instantly sets off a series of caspase enzymes that help initiate apoptosis (cell death). "Our study shows how cancer cells manage to offset the impact of low-glucose tumor microenvironments, and how these changes in cancer cell metabolism minimize chemotherapy's effectiveness," said study lead investigator Minwoo Nam, PhD, a postdoctoral fellow in the Department of Pathology at NYU Grossman School of Medicine and Perlmutter Cancer Center. "Our results explain what has until now been unclear about how the altered metabolism of the tumor microenvironment impacts chemotherapy: low glucose slows down the consumption and exhaustion of uridine nucleotides needed to fuel cancer cell growth and hinders resulting apoptosis, or death, in cancer cells," said senior study investigator Richard Possemato, PhD. Possemato is an associate professor in the Department of Pathology at NYU Grossman School of Medicine and also a member of Perlmutter Cancer Center. Possemato, who is also coleader of the Cancer Cell Biology Program at Perlmutter, says his team's study results could one day be used to develop chemotherapies or combination therapies that would change or trick cancer cells into responding the same way in a low-glucose microenvironment as they would in an otherwise stable glucose microenvironment. He also says that diagnostic tests could be developed to measure how a patient's cancer cells would most likely respond to low-glucose microenvironments and to predict how well a patient might respond to a particular chemotherapy. Possemato says his team has plans to investigate how blocking other cancer cell pathways might trigger apoptosis in response to these chemotherapies. Some experimental drugs, such as Chk-1 and ATR inhibitors, already exist that might accomplish this, he notes, but more need to be investigated because Chk-1 and ATR inhibitors are not well tolerated by patients. For the study, researchers performed a scan of 3,000 cancer cell genes known to be involved in cell metabolism to determine, by deletion, which were necessary for cancer cell survival after chemotherapy. Most of the genes they found that were essential to cell survival in low-glucose tumor environments were also involved in pyrimidine synthesis, a precise biological pathway targeted by many chemotherapies. This focused their experiments on how different lab-grown clones of cancer cells responded to low-glucose after chemotherapy and what other chemical processes were impacted by depressed sugar levels. Funding support for the study was provided by National Institutes of Health grants P30CA016087, R01CA286141, R01CA214948, R01GM132491, and R35GM139610. Additional funding support came from the Pew Charitable Trusts, Alexander and Margaret Stewart Trust, and the American Cancer Society. Besides Nam and Possemato, other NYU Langone researchers involved in this study are co-investigators Wenxin Xia, Abdul Hannan Mir, and Tony Huang. Media Inquiries: David March 212-404-3528 [email protected] STUDY LINK WILL BECOME ACTIVE AFTER EMBARGO LIFTS: STUDY DOI: 10.1038/s42255-024-01166-w SOURCE NYU Langone Health System WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED