Details

Autor(en) / Beteiligte

• Pal, Sanjay
• Medatwal, Nihal
• Kumar, Sandeep
• Kar, Animesh
• Komalla, Varsha
• Yavvari, Prabhu Srinivas
• Mishra, Deepakkumar
• Rizvi, Zaigham Abbas
• Nandan, Shiv
• Malakar, Dipankar
• Pillai, Manoj
• Awasthi, Amit
• Das, Prasenjit
• Sharma, Ravi Datta
• Srivastava, Aasheesh
• Sengupta, Sagar
• Dasgupta, Ujjaini
• Bajaj, Avinash

Titel

A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

Ist Teil von

• ACS central science, 2019-10, Vol.5 (10), p.1648-1662

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Rapid proliferation of cancer cells assisted by endothelial cell-mediated angiogenesis and acquired inflammation at the tumor microenvironment (TME) lowers the success rate of chemotherapeutic regimens. Therefore, targeting these processes using localized delivery of a minimally toxic drug combination may be a promising strategy. Here, we present engineering of a biocompatible self-assembled lithocholic acid-dipeptide derived hydrogel (TRI-Gel) that can maintain sustained delivery of antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and anti-inflammatory dexamethasone. Application of TRI-Gel therapy to a murine tumor model promotes enhanced apoptosis with a concurrent reduction in angiogenesis and inflammation, leading to effective abrogation of tumor proliferation and increased median survival with reduced drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel therapy induced transcriptome-wide alternative splicing of many genes responsible for oncogenic transformation including sphingolipid genes. We demonstrate that TRI-Gel therapy targets the reversal of a unique intron retention event in β-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein. An enhanced Gba1 activity elevates ceramide levels responsible for apoptosis and decreases glucosylceramides to overcome drug resistance. Therefore, TRI-Gel therapy provides a unique system that affects the TME via post-transcriptional modulations of sphingolipid metabolic genes, thereby opening a new and rational approach to cancer therapy.