title: Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization.
abstract: This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ's are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 µM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50of 30 µM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochon-drial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.
authors.affiliation: Universidad Metropolitana, San Juan, Puerto Rico.
authors.forename: Christian
authors.initials: C
authors.lastname: Vélez
authors.affiliation: Universidad Metropolitana, San Juan, Puerto Rico.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Cox
authors.affiliation: Arkansas State University, Jonesboro, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rosado-Berrios
authors.affiliation: Universidad Metropolitana, San Juan, Puerto Rico.
authors.forename: Dennise
authors.initials: D
authors.lastname: Molina
authors.affiliation: Universidad Metropolitana, San Juan, Puerto Rico.
authors.forename: Luz
authors.initials: L
authors.lastname: Arroyo
authors.affiliation: University of North Carolina, Chapel Hill, USA.
authors.forename: Sujey
authors.initials: S
authors.lastname: Carro
authors.affiliation: Laboratory of Synthetic Chemistry-SAIC, Frederick National Laboratory for Cancer Research, Frederick, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Filikov
authors.affiliation: Laboratory of Synthetic Chemistry-SAIC, Frederick National Laboratory for Cancer Research, Frederick, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Laboratory of Synthetic Chemistry-SAIC, Frederick National Laboratory for Cancer Research, Frederick, USA.
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Malhotra
authors.affiliation: University of Puerto Rico, San Juan, USA.
authors.forename: Marisol
authors.initials: M
authors.lastname: Cordero
authors.affiliation: Universidad Metropolitana, San Juan, Puerto Rico.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Zayas
keywords: A431; Apoptosis; Caspase Activation; Mutagenesis; Quinolinium Salts