Exploiting the ferroaddiction of pancreatic cancer cells using Fe-doped nanoparticles

IF 4.2 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Thanpisit Lomphithak M.Sc. , Apiwit Sae-Fung M.Sc. , Simone Sprio Ph.D. , Anna Tampieri Ph.D. , Siriporn Jitkaew Ph.D. , Bengt Fadeel M.D., Ph.D.
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引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor survival rates. Here, we evaluated iron-doped hydroxyapatite (FeHA) as a potential nanomedicine-based approach to combat PDAC. FeHA, in combination with a sublethal dose of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, was found to trigger ferroptosis in KRAS mutant PANC-1 cells, but not in BxPC3 cells, while sparing normal human cells (fibroblasts and peripheral blood mononuclear cells). These findings were recapitulated in 3D spheroids generated using PDAC cells harboring wild-type versus mutant KRAS. Moreover, ferroptosis induction by FeHA plus RSL3 was reversed by the knockdown of STEAP3, a metalloreductase responsible for converting Fe3+ to Fe2+. Taken together, our data show that FeHA is capable of triggering cancer cell death in a KRAS-selective, STEAP3-dependent manner in PDAC cells.

Abstract Image

利用掺铁纳米颗粒研究胰腺癌细胞的铁依赖性
胰腺导管腺癌(PDAC)是一种生存率低的毁灭性疾病。在这里,我们评估了铁掺杂羟基磷灰石(FeHA)作为一种潜在的基于纳米医学的方法来对抗PDAC。研究发现,FeHA与亚致死剂量的谷胱甘肽过氧化物酶4 (GPX4)抑制剂RSL3联合使用可触发KRAS突变体PANC-1细胞的铁凋亡,但在BxPC3细胞中没有,而正常的人类细胞(成纤维细胞和外周血单核细胞)则不受影响。这些发现在使用PDAC细胞生成的3D球体中得到了概括,这些细胞含有野生型和突变型KRAS。此外,FeHA + RSL3诱导的铁死亡可以通过敲低STEAP3(一种负责将Fe3+转化为Fe2+的金属还原酶)而逆转。综上所述,我们的数据表明FeHA能够在PDAC细胞中以kras选择性、steap3依赖性的方式触发癌细胞死亡。
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来源期刊
CiteScore
11.10
自引率
0.00%
发文量
133
审稿时长
42 days
期刊介绍: The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.
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