Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice

Abstract

The anti-tumour activity of acriflavine in combination with guanosine has been evaluated in solid or ascitic tumour-implanted animal models. Guanosine is known to potentiate the anti-tumour effects of some chemotherapeutic agents. Administration of acriflavine (15 mg kg-1 day-1, i.m., 14 days) to ICR mice subcutaneously implanted with Ehrlich carcinoma resulted in approximately 30% inhibition in tumour growth. In contrast, minor tumour growth inhibition was observed in animals treated with guanosine at the same daily dose. Treatment of animals with both acriflavine and guanosine (AG60, 1:1, w/w) at 30 mg kg-1 resulted in approximately 65% inhibition in tumour growth rate. Whereas treatment with acriflavine or guanosine resulted in 70% or 30% decrease in tumour weight, respectively, treatment of tumour-implanted mice with AG60 (30 mg kg-1) resulted in a 96% decrease in tumour weight, relative to control, 14 days after tumour-cell implantation. Dose-related inhibition in tumour growth rate was also observed in animals treated with AG60, with maximum (65%) inhibition noted at a dose of 30 mg kg-1 (ED50 23 mg kg-1). Suppression of body weight increase and elevated plasma glucose levels by acriflavine or AG60 indicated that glucose utilization might be impaired. The anti-tumour effect of AG60 was also determined in CDF1 mice intraperitoneally implanted with Ehrlich ascitic tumour. Ehrlich ascitic tumour proliferation was completely suppressed by AG60 (30 mg kg-1, i.p.). Microscopic analyses of intraperitoneal touch-prints revealed that AG60 was more effective in suppressing tumour proliferation than acriflavine alone. Fluorescent microscopic examinations demonstrated that acriflavine avidly bound with Yac-1 cell plasma membrane, leading to morphological changes in the cells, such as bleb formations, swelling and ballooning. The time-related changes in tumour cell morphology by acriflavine or AG60 might represent energy depletion, followed by osmotic lysis as a result of cationic influx. Enhanced anti-tumour activity of acriflavine in combination with guanosine might be explained by the blocking of nutrient transport through selective acriflavine binding with plasma membrane and by concomitant guanosine perturbation of cellular ATP production. This study demonstrates that guanosine enhances the anti-tumour effects of acriflavine against a variety of cancer cells without serious adverse effects, providing a preclinical basis for potential application of this combination against cancer proliferation.

Novel activity of acriflavine against colorectal cancer tumor cells

“…(24)(25)(26)(27) In these models, acriflavine has a short pharmacokinetic half-life, reaches peak plasma concentrations well above the IC 50 values observed in the present investigation and is generally well tolerated. (24)(25)(26)(27)(28) With this background, further clinical development of acriflavine as a cancer drug seems considerably easier than the development of a new chemical entity.…”

Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury

“…Guanosine (Sigma Chemical Co., St. Louis, Missouri, USA), 30 mg/kg in 0.9% NaCl, or an equal volume of 0.9% NaCl was administered via intraperitoneal injection. The dose of guanosine was based on the in vivo use of nucleosides from cancer literature (13). Male C57 black mice weighing 15-25 g and Sprague-Dawley rats weighing 180-220 g (Harlan, Indianapolis, Indiana, USA) were anesthetized with intraperitoneal sodium pentobarbital (50-70 mg/kg) and placed on a homeothermic table to maintain core body temperature at 37°C.…”

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells

“…n = 6 of independent experiments for a, b, and c separately. *p < 0.05 compared to the control group 10 days with 15 mg/kg/day GUO and it caused a 30% reduction of tumor weight [32]. The association of GUO with acriflavine treatment in vivo demonstrated and enhanced acriflavine antitumoral effect, by decreasing 96% of tumor weight [32].…”