Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.
Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.
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钙通道阻滞剂增强吉西他滨治疗胰腺癌的疗效。
DOI：
10.1073/pnas.2200143119
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发表时间：
2022-05-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
胰腺癌是癌症相关死亡的主要原因，部分原因是对标准治疗化疗的不完全反应。在这项研究中，使用单细胞RNA测序和高通量蛋白质组学的组合，我们确定了钙响应蛋白钙调素作为一线化疗药物吉西他滨耐药的关键介质。钙调蛋白的抑制导致体外吉西他滨耐药性的丧失，这是使用钙螯合剂或食品和药物管理局批准的钙通道阻滞剂（CCB），包括顺铂重演。在动物研究中，顺铂显著增强了对吉西他滨化疗的治疗反应，降低了远处转移的发生率，延长了生存期。因此，纳入CCB可能提供一种安全有效的方法来改善胰腺癌患者对吉西他滨化疗的反应。胰腺导管腺癌（PDAC）目前尚无有效的治疗方法。虽然姑息化疗为大多数患者提供了生存益处，但几乎所有患者最终都会在治疗中取得进展，长期生存能力仍然很差。鉴于缺乏后续线治疗选择，在这项研究中，我们试图确定新的策略，以预防，延迟或克服耐药性吉西他滨，PDAC中最广泛使用的药物之一。使用单细胞RNA测序和高通量蛋白质组学分析的组合，我们确定了一个子集的吉西他滨耐药肿瘤细胞富集钙/钙调蛋白信号。钙依赖性钙调蛋白激活的药理学抑制导致体外耐药表型的快速丧失，额外的单细胞RNA测序鉴定是由于RAS/ERK信号通路的激活受损。与这些观察结果一致，培养基中的钙螯合或钙消耗也损害了吉西他滨耐药细胞中的ERK活化，并恢复了体外对吉西他滨的治疗反应。我们观察到类似的结果，使用钙通道阻滞剂（CCBs），如在体外抑制促生存ERK信号转导，并显着增强吉西他滨在原位异种移植和转基因模型的PDAC的治疗反应。综合起来，这些结果提供了对吉西他滨耐药的潜在手段的深入了解，并表明选择CCB可能为接受基于吉西他滨的化疗的PDAC患者提供临床获益。
Pancreatic cancer is a leading cause of cancer-related death, in part due to incomplete responses to standard-of-care chemotherapy. In this study, using a combination of single-cell RNA sequencing and high-throughput proteomics, we identified the calcium-responsive protein calmodulin as a key mediator of resistance to the first-line chemotherapy agent gemcitabine. Inhibition of calmodulin led to the loss of gemcitabine resistance in vitro, which was recapitulated using a calcium chelator or Food and Drug Administration–approved calcium channel blockers (CCBs), including amlodipine. In animal studies, amlodipine markedly enhanced therapeutic responses to gemcitabine chemotherapy, reducing the incidence of distant metastases and extending survival. Hence, incorporating CCBs may provide a safe and effective means of improving responses to gemcitabine-based chemotherapy in pancreatic cancer patients. There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.
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去甲肾上腺素和前列腺素 F2 α 在肝细胞中 Ca2+ 介导的 ERK 激活：钙调蛋白和 Src 激酶的作用。
影响因子：
--
作者：
Melien O;Nilssen LS;Dajani OF;Sand KL;Iversen JG;Sandnes DL;Christoffersen T
通讯作者：
Christoffersen T
DOI：
10.1016/s0169-328x(99)00280-6
发表时间：
2000-01-10
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Lee, SA;Park, JK;Park, HT
通讯作者：
Park, HT
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
11.1
作者：
Kanwar, Nisha;Carmine-Simmen, Katia;Done, Susan J.
通讯作者：
Done, Susan J.