肝母细胞瘤化疗耐药机制中转运体的相关性。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-04-02 DOI:10.1016/j.bcp.2025.116914

Candela Cives-Losada , Maitane Asensio , Oscar Briz , Luis Miguel Chinchilla-Tábora , María Manuela Barranco , Álvaro del Río-Álvarez , Maria Luz Martinez-Chantar , Matias A. Avila , Stefano Cairo , Carolina Armengol , Jose J.G. Marin , Rocio I.R. Macias

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引用次数: 0

摘要

大约20% %的肝母细胞瘤（HBs）由于化疗耐药（MOCs）机制，如细胞内药物积累减少，对常规化疗反应较差。本研究评估了转运体在HB多药耐药（MDR）中的作用。对配对的HB和邻近的肝组织样本（n = 19）以及HB来源的细胞系（HepG2, HuH6）进行mRNA （RT-qPCR, Taqman Low-Density Array，测序）和蛋白质（western blot，免疫组织化学，免疫荧光）水平的抗性组鉴定。测定细胞活力（MTT法）、增殖和迁移（全息显微镜法）。研究了HB细胞暴露于顺铂或阿霉素的短期（72 h）和长期（10 个月）对转运体的影响。溶质载体（SLC）转运蛋白家族在HB MDR中表现出较小的相关性，而药物出口泵，特别是MRP2，与化疗不良反应相关。暴露于阿霉素或顺铂的HB细胞上调MDR1、MRP1和MRP2。在诱导持续化疗耐药的细胞中，参与其他MOCs的基因表达和表观遗传机制发生了改变。化疗耐药细胞对几种抗癌药物表现出交叉耐药，但对卡博赞替尼保持敏感性。总之，药物出口泵，而不是SLC摄取转运体，是HB耐药的关键因素。Cabozantinib成为传统化疗耐药肿瘤的潜在治疗选择。

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Relevance of transportome among the mechanisms of chemoresistance in hepatoblastoma

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Relevance of transportome among the mechanisms of chemoresistance in hepatoblastoma

Approximately 20 % of hepatoblastomas (HBs) exhibit a poor response to conventional chemotherapy due to mechanisms of chemoresistance (MOCs), such as reduced intracellular drug accumulation. This study evaluated the role of transportome in the multidrug resistance (MDR) of HB. Paired HB and adjacent liver tissue samples (n = 19) and HB-derived cell lines (HepG2, HuH6) were analyzed for their resistome characterization at mRNA (RT-qPCR, Taqman Low-Density Array, sequencing) and protein (western blot, immunohistochemistry, immunofluorescence) levels. Cell viability (MTT test) proliferation and migration (holographic microscopy) were determined. The impact of short-term (72 h) and long-term (>10 months) exposure of HB cells to cisplatin or doxorubicin on the transportome was investigated. Solute carrier (SLC) family of transporters showed minor relevance in HB MDR, while drug export pumps, particularly MRP2, were associated with poor response to chemotherapy. Exposure of HB cells to doxorubicin or cisplatin up-regulated MDR1, MRP1 and MRP2. In cells with induced persistent chemoresistance, the expression of genes involved in other MOCs, and epigenetic machinery was altered. Chemoresistant cells showed cross-resistance to several anticancer drugs but maintained sensitivity to cabozantinib. In conclusion, drug export pumps, but not SLC uptake transporters, are key contributors to HB chemoresistance. Cabozantinib emerges as a potential therapeutic option for HBs resistant to conventional chemotherapy.

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.