An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities

Abstract

We describe the biological activity of some furylbenzo- and naphthoquinones (furylquinones) on hepatocarcinoma cells and healthy rat liver slices. The effects of furylquinones on cancer cells (Transplantable Liver Tumor, TLT) were assessed by measuring cell death (membrane cell lysis); intracellular contents of ATP and GSH and the activity of caspase-3 were used to determine the type of cell death. Most of the furylquinones tested (at a concentration of 25 μg/ml) induced caspase-independent cell death but compound 4 had no cytotoxic effects. The levels of both ATP and GSH were severely affected by quinones 1, 2 and 5, while no effect was observed with compound 4. These cytotoxic properties of quinones are associated with physico-chemical properties as shown by the LUMO energies and lipophilicity. Interestingly, no cytotoxic effects of furylquinones were detected when the in vitro model of precision-cut liver slices (PCLS) was used. Indeed, although CYP2E1 activity was slightly affected, ATP and GSH levels as well as protein synthesis were not modified by furylquinones. Paracetamol, a well-known hepatotoxicant, reduced these parameters by more than 80% compared to control conditions. Taking into account the considerable incidence of adverse-effects induced by most current anticancer drugs, the selective cytotoxicity shown by compounds 1, 2 and 5, in particular that of 1, represents a safety factor that encourages the further development of these quinones as new drugs in cancer therapy.

Replacement of a Quinone by a 5-O-Acetylhydroquinone Abolishes the Accidental Necrosis Inducing Effect while Preserving the Apoptosis-Inducing Effect of Renieramycin M on Lung Cancer Cells

“…Several studies suggested that the quinone group is responsible for the ROS-inducing action. − Accordingly, many quinone-containing antitumor agents, such as adriamycin, daunorubicin, actinomycin D, mitomycin C, and trenimon, were shown to mediate DNA strand breaks and cell death via an ROS-dependent mechanism. ,− Free radicals and highly reactive molecules, including superoxide radicals, hydroxyl radicals, semiquinones, and hydrogen peroxide, were found in cells treated with quinone-containing compounds, and those molecules were proved to induce necrosis . Indeed, menadione, a redox-active naphthoquinone, was shown to induce necrosis by damaging plasma membrane integrity via a free radical mediated process. , In addition, furylquinones underwent an activation process via a redox mechanism causing necrosis in TLT hepatoma cells. , As mentioned earlier, ROS are hypothesized as one of the key factors for necrosis in response to several stimuli, and the quinone moiety is recognized as a radical generator. ,− To test whether ROS played a role in the renieramycin M and 5- O -acetylated hydroquinone derivative mediated cell deaths, the strong antioxidant N -acetylcysteine (NAC 1 mM) was used. The cells were pretreated with NAC prior to 1 and 2 treatments, and cell viability at 24 h was determined.…”

“…47,48 In addition, furylquinones underwent an activation process via a redox mechanism causing necrosis in TLT hepatoma cells. 47,49 As mentioned earlier, ROS are hypothesized as one of the key factors for necrosis in response to several stimuli, 30 and the quinone moiety is recognized as a radical generator. 44,50−52 To test whether ROS played a role in the renieramycin M and 5-O-acetylated hydroquinone derivative mediated cell deaths, the strong antioxidant N-acetylcysteine (NAC 1 mM) was used.…”

Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death

“…As part of our study of new quinones with potential antitumor activity [10][11][12][13], we recently reported that some phenylaminopyrimido [4,8-c]isoquinolinequinones (APIQ) and their precursors 1 and 2 have in vitro antitumor activity [14], which is enhanced in the presence of a relevant and well-known reducing agent, i.e., ascorbate [15]. These findings, together with the broad range of antitumor activities observed in the aryl-and alkylaminopyrimido [4,8-c]isoquinolinequinones series, led to the suggestion that the observed biological activity is related to the redox properties of these aminoquinones.…”

Caspase‐3: A primary target for natural and synthetic compounds for cancer therapy

“…Conversely, Benites et al., (2011) reported a series of furylbenzo‐ and naphthoquinones (furylquinones) derivatives for caspase‐independent cytotoxicity in rat liver slices.…”