Anticancer Effect of a Spiro-acridine Compound Involves Immunomodulatory and Anti-angiogenic Actions

Abstract

Background/Aim: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4chlorobenzylidene)amino)-5 -4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. Materials and Methods: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. Results: AMTAC-06 did not induce toxicity on zebrafish and mice (LD 50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G 1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an antiangiogenic action, possibly dependent on the cytokine modulation . No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. Conclusion: AMTAC-06 has low toxicity and a significant antitumor activity.The mechanisms underlying the transformation of normal cells into malignant cells have been thoroughly studied, aiming to better understand the biology of cancer and develop new treatments. Researchers have described common traits acquired during tumorigenesis, including sustaining proliferative signaling, induction of angiogenesis, deregulation of cell cycle, resistance to cell death and tumorpromoting inflammation (1-3). These hallmarks are important therapeutic targets for new antitumor drug development (3,4).Acridines are heterocyclic molecules containing a planar ring, which have shown anti-inflammatory, anticancer, antiparasitic, antiviral, and antimicrobial activities, among others (5). Their antitumor action is based on DNA binding and topoisomerase inhibition (6), which may cause apoptosis and cell cycle arrest (7). Nevertheless, acridine compounds 5049

A 9-aminoacridine derivative induces growth inhibition of Ehrlich ascites carcinoma cells and antinociceptive effect in mice

“…Therefore, this dose was chosen to study the toxicological, antiangiogenic, and immunomodulatory actions, as well as the modulation of oxidative stress in the EAC model. Our findings are consistent with literature reports which have shown the antitumor potential of other acridine derivatives, including alkylamino-acridine derivatives ( Cholewiński et al, 2011 ), spiro-acridines ( Silva et al, 2019 ; Duarte et al, 2020 ), and 9-aminoacridine derivatives ( Belmont and Dorange, 2008 ; Mangueira et al, 2017 ; Kozurkova et al, 2020 ; Kumar et al, 2013 ; Rupar et al, 2020 ; El-Sayed et al, 2022 ).…”

“…The acridine scaffold has attracted attention in oncology since its DNA affinity and intercalative properties make it an important pharmacophore for the design of antitumor drugs targeting DNA ( Denny, 2002 ; Belmont and Dorange, 2008 ; Fu et al, 2017 ; Lambert et al, 2018 ; Duarte et al, 2020 ; Oyedele et al, 2020 ; Majhi, 2022 ; Silva et al, 2019 ). In this regard, we can highlight the 9-aminoacridine derivatives, which have shown potential anticancer, antinociceptive, and against neurodegenerative diseases and protozoal parasites.…”

“…with ACS-AZ (12.5, 25, or 50 mg/kg/day) for seven consecutive days. The doses and duration of treatments were chosen from literature reports for acridine compounds in the same experimental model ( Duarte et al, 2020 ; Lisboa et al, 2020 ; Silva et al, 2020 ). The remaining two groups were treated with 5-Fluorouracil - 5-FU (25 mg/kg), as the standard drug, and vehicle alone (Tween 80 at 12% (v/v) in saline), the control group ( Dolai et al, 2012 ).…”

“…For sample size calculation, the expected effect size was obtained from a previous study ( Duarte et al, 2020 ). Using a 1% significance level, Hedge’s of 2.514 (effect size), the statistical power of 90%, and sample loss of 30%, the required sample size was eight mice per group.…”

“…We have previously reported two spiro-acridine derivatives, a thiophene–acridine hybrid, and a 9-aminoacidrine derivative as potential anticancer agents ( Duarte et al, 2020 ; Lisboa et al, 2020 ; Mangueira et al, 2017 ; Silva et al, 2019 ). The anticancer potential of the spiro-acridine compounds was associated with antiangiogenic action and up-regulation of Th1-type responses, mainly by inducing the increase of TNF-α and IL-1β levels in the tumor microenvironment ( Duarte et al, 2020 ; Silva et al, 2020 ). We also published the synthesis and antitumor effect of a new 9-aminoacridine derivative by inducing cell cycle arrest and angiogenesis ( Mangueira et al, 2017 ).…”