帕比司他与多柔比星联合治疗软组织肉瘤的协同作用。

Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas.

机构信息

Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.

Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory in Translational Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Cancer Drug Testing Unit, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.

出版信息

Biomed Pharmacother. 2024 Jul;176:116895. doi: 10.1016/j.biopha.2024.116895. Epub 2024 Jun 14.

DOI:10.1016/j.biopha.2024.116895

PMID:38876055

Abstract

BACKGROUND

Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS.

METHODS

Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays.

RESULTS

Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

摘要

背景

软组织肉瘤（STS）是一种罕见的疾病，通常发生于儿童和成人的结缔组织中。然而，STS 治疗中涉及的化疗可能会引起毒性副作用和多药耐药性，使得治疗更加具有挑战性。组蛋白去乙酰化酶抑制剂（HDACi）是一种表观遗传药物，已被证明具有单药和与其他药物联合使用的抗肿瘤作用。我们的项目旨在证明其在 STS 中的同样效果。

方法

基于我们之前的研究，选择泛昔洛韦（LBH589）加多柔比星进行研究。在一个上皮样肉瘤模型中尝试肿瘤异种移植物，以验证体内的良好协同作用，并使用平滑肌肉瘤模型作为阴性对照组。随后研究了基因谱的变化。通过几种测定方法探讨并验证了 HDACi 引起的可能途径变化。

结果

LBH589 加多柔比星的协同作用在 STS 细胞系和上皮样肉瘤小鼠模型中得到了成功验证。我们试图降低多柔比星的剂量至较低水平，发现药物联合仍能抑制小鼠肿瘤的大小。此外，通过 RNA 测序分析研究了 LBH589 引起的基因谱变化。结果表明，LBH589 可以对一组靶基因发挥作用，这些基因可以调节潜在的生物学功能，特别是在细胞周期途径中。