Anticancer Activities of DNA-Alkylating Pyrrole-Imidazole Polyamide Analogs Targeting RUNX Transcription Factors against p53 -Mutated Pancreatic Cancer PANC-1 Cells.
Yuki HiroseShinsuke SatoKaori HashiyaToshikazu BandoHiroshi SugiyamaPublished in: Journal of medicinal chemistry (2023)
The runt-related transcription factor (RUNX) family is known to play important roles in the progression of cancer. Conjugate 1 , which covalently binds to the RUNX-binding sequences, was reported to inhibit the binding of RUNX proteins to their target sites and suppress cancer growth. Here, we evaluated the anticancer effects of 1 and its analogs 2 - 4 against p53 -mutated PANC-1 pancreatic cancer cells. We found that they possessed different DNA-alkylating properties in vitro . And conjugates 1 - 3 were shown to have anticancer effects by inducing apoptosis in PANC-1 cells. Furthermore, conjugates 2 and 3 suppressed cancer growth in PANC-1 xenograft mice, with activity equivalent to a 50-fold dose of gemcitabine. Especially, 3 showed the highest alkylation efficiency, specificity, and better anticancer effects against pancreatic cancer than 1 in vivo without significant body weight loss. Our results revealed the potential of our compounds as new candidates for cancer therapy.
Keyphrases
- transcription factor
- cancer therapy
- dna binding
- papillary thyroid
- cell cycle arrest
- induced apoptosis
- squamous cell
- weight loss
- drug delivery
- cell death
- bariatric surgery
- oxidative stress
- endoplasmic reticulum stress
- single molecule
- circulating tumor
- molecular docking
- body mass index
- childhood cancer
- signaling pathway
- lymph node metastasis
- young adults
- genome wide identification
- climate change
- weight gain
- drug induced