Anticancer Activities of DNA-Alkylating Pyrrole–Imidazole Polyamide Analogs Targeting RUNX Transcription Factors against p53-Mutated Pancreatic Cancer PANC-1 Cells

Abstract

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.

Chb-M′, an Inhibitor of the RUNX Family Binding to DNA, Induces Apoptosis in p53-Mutated Non-Small Cell Lung Cancer and Inhibits Tumor Growth and Repopulation In Vivo

“…By treating cells with 0.3 or 3 μM of the compound, cell populations shifted to the lower right (early apoptotic cells) and upper right (late apoptotic cells) parts of the plot (Figure ). This indicated that Chb-M′ killed p53 -mutated NSCLC cells by inducing apoptosis, as it did in other p53 -WT and p53 mutant cancer cells. ,, …”

“…In spite of the anticancer effect of Chb-M′ against NCI-H2228-Luc cells, when we conducted the same experiment with BJ cells (human normal fibroblast cell line) to evaluate the toxicity of the compounds, all compounds did not show any toxicity against this cell line after treatment for 3 days (Figure S5). Although this result suggested the low toxicity of Chb-M′ against normal cells, it is also the fact that this compound decreased the viability of human normal pancreas duct cells (viability was ∼80%) in our previous research . It is still less toxic than that against NCI-H2228-Luc cancer cells, but evaluation of the toxicity of this compound should be performed in more detail in the future.…”

“…Chb-M′ (OH) was synthesized as described previously . After workup, HPLC purification, and lyophilization, Chb-M′ (OH) was obtained as an off-white powder.…”

“…The fact that Chb-M′ showed a higher anticancer effect against MV4-11 cells than that of Chb alone and a Chb-inactivated compound , indicated that the combination of the DNA-alkylating agent and DNA-recognizing compound is crucial for effective anticancer activity. Early studies suggested that Chb-M′ was effective against cancers with WT p53 , but recently, examples of its effectiveness against cancers with mutations in p53 have been reported. , Because approximately 50% of cancers have p53 mutations, , these results indicate that compounds targeting the RUNX-consensus sequence could be attractive therapeutic options for a wide range of cancer types.…”

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

“…Apoptosis produces cellular alterations, such as phosphatidylserine (PS) translocation from inside to outside the plasma membrane. Annexin-V, a sensitive probe that binds to PS, may detect it outside the plasma membrane. , We performed cytometric analysis using the BD FACSCalibur (BD Biosciences, San Jose, CA) to distinguish between the apoptotic and necrotic modes of pancreatic PANC1 cells’ death as a result of the most active compound, 5e . Figure S59 shows the outcomes of compound 5e ’s 24 h treatment of PANC1 cells.…”