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Discovery of Mitochondrial Transcription Inhibitors Active in Pancreatic Cancer Cells
Author(s) -
Chen Wenmin,
Hu Shuai,
Mao Shuai,
Xu Yibin,
Guo Hui,
Li Haoxi,
Paulsen Michelle T.,
Chen Xinde,
Ljungman Mats,
Neamati Nouri
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000494
Subject(s) - mitochondrion , oxidative phosphorylation , mitochondrial dna , transcription factor , biology , cancer cell , microbiology and biotechnology , oxidative stress , transcription (linguistics) , chemistry , cancer research , biochemistry , cancer , gene , genetics , linguistics , philosophy
Mitochondrial dysfunction is a hallmark of cancer cells and targeting cancer mitochondria has emerged as a promising anti‐cancer therapy. Previously, we repurposed chlorambucil by conjugating it to a mitochondrial targeting triphenylphosphonium (TPP) group to design Mito‐Chlor, a novel agent that acts on mitochondria DNA (mtDNA). Herein, we show that Mito‐Chlor, but not chlorambucil, inhibits the nascent transcription of mtDNA. Clustering analysis of transcriptomic profile of our Bru‐seq database led to the identification of another mitochondrial transcription inhibitor SQD1, which inhibits the proliferation of MIA PaCa‐2 cells with an IC 50 of 1.3 μM. Interestingly, Mito‐Chlor reduces expression of mitochondrial proteins, interferes with mitochondria membrane potential, and impairs oxidative phosphorylation while SQD1 does not. Both compounds increased cellular and mitochondrial reactive oxygen species and stimulated similar signaling pathways in response to oxidative stress. As mitochondrial transcription inhibitors and redox modulators, SQD1 and Mito‐Chlor are promising for the treatment of pancreatic cancer by blocking mitochondrial function.