Abstract
The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide G4-binding molecule (CM03) with selective potency for pancreatic cancer cells, including gemcitabine-resistant cells. We report here that CM03 and the histone deacetylase (HDAC) inhibitor SAHA (suberanilohydroxamic acid) have synergistic effects at concentrations close to and below their individual GI50 values, in both gemcitabine-sensitive and resistant pancreatic cancer cell lines. Immunoblot analysis showed elevated levels of γ-H2AX and cleaved PARP proteins upon drug combination treatment, indicating increased levels of DNA damage (double-strand break events: DSBs) and apoptosis induction, respectively. We propose that the mechanism of synergy involves SAHA relaxing condensed chromatin, resulting in higher levels of G4 formation. In turn, CM03 can stabilise a greater number of G4s, leading to the downregulation of more G4-containing genes as well as a higher incidence of DSBs due to torsional strain on DNA and chromatin structure.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA and is expected to be the second or the third in developed and high-income countries in the ten years [1]
We have recently developed a class of potential drugs for Pancreatic Ductal AdenoCarcinoma (PDAC) that are based on the naphthalene diimide (ND) chemotype [3,4]
The lead compounds CM03 and SOP1812 have shown profound in vitro anti-proliferative activity in pancreatic cancer cell lines and significant in vivo anti-tumour activity in several PDAC models, with an improved profile compared to gemcitabine [5,6,7,8,9]
Summary
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA and is expected to be the second or the third in developed and high-income countries in the ten years [1]. HDAC lymphomas and panobinostat for multiple myeloma) have received regulatory approval for clinical inhibitors Several inhibitors (for panobinostat) example, SAHA panobinostat) are treatment of potential use in the cancer [32,33,34,35,36,37] Their mode of action involves increasing acetylation by inhibiting histone deacetylase treatment of pancreatic cancer [32,33,34,35,36,37]. We have used the clinically approved HDAC drug SAHA to investigate potential synergistic effects with a potent G4 binding compound, the naphthalene diimide compound CM03, which was developed in these laboratories [8]
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