Toxicity of daunorubicin and naphthoquinones to HL‐60 cells: an involvement of oxidative stress

Abstract

Incubation of HL‐60 cells with anthracycline daunorubicin caused an appearance of viable apoptotic, nonviable apoptotic, necrotic (nonviable nonapoptotic) and chromatin‐free (late apoptotic) cells. Both necrotic and apoptotic cell responses were partly prevented by antioxidant N,N′‐diphenyl‐p‐phenylene diamine (DPPD) and iron‐chelating agent, desferrioxamine, suggesting an involvement of activated oxygen species. The comparison of cytotoxicity of daunorubicin and of 5‐hydroxy‐ and 5,8‐dihydroxy‐1,4‐naphthoquinones revealed that at equitoxic concentrations, hydroxynaphthoquinones induced a larger number of necrotic cells in comparison to daunorubicin, a process being partly prevented by DPPD and desferrioxamine. However, we have found that cytotoxicity of daunorubicin was markedly higher in comparison with a series of naphtho‐ and benzoquinones, where an increase of cytotoxicity upon increase in single‐electron reduction potential of quinones (E17) was observed, pointing out to redox cycling as to the main factor of cytotoxicity. This discrepancy could be explained by additional factor(s) of daunorubicin cytotoxicity, e.g. DNA‐intercalation, or selective accumulation of daunorubicin in cell nucleus.

Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

“…The cytotoxic effects of daunorubicin are related to reactive oxygen species (ROS) generated during enzymatic reactions or redox cycling of anthracyclines, although it may act through the DNA damage induced by the direct binding of daunorubicin molecule to DNA as well (Minotti et al 2004;Dickancaite et al 1997). Both ROS and DNA damage have been shown to be mediators of JNK activation in response to multiple and diverse stress factors (Shen and Liu 2006;Damrot et al 2009).…”

“…It is known that apoptosis has been implicated in acute and chronic cardiac diseases (Clerk et al 2003;Garg et al 2003). There are reports that anthracyclines, including daunorubicin, cause both apoptotic and necrotic cell death (Dickancaite et al 1997;Nobori et al 2002). The initiation of programmed cell death by various anticancer drugs activates protein kinase cascades showing their involvement in apoptosis.…”

Structure‐activity relationships in the haemolytic activity and nephrotoxicity of derivatives of 1,2‐ and 1,4‐naphthoquinone

“…Effects on NQO1 activity are not correlated with toxicity. It should also be noted that in vitro cytotoxicity assays cannot accurately predict in vivo toxicity, since 2-hydroxy-1,4-naphthoquinone has been shown to be much less toxic than 2-methyl-1,4-naphthoquinone in a variety of cell types (Diçkancaite et al, 1997;Stubblefield and Cohen, 1989;Noda et al, 1997), yet the reverse is true in vivo. Similarly, dialkyl naphthoquinones show little effect in vitro, but are powerful haemolytic agents in rats (Munday et al, 1995a).…”

Quinones as photosensitizer for photodynamic therapy: ROS generation, mechanism and detection methods

“…Thus oxygen-derived species are mutagenic 20,21 and may act as promotors of carcinogenesis. 22,23 ROS are also implicated in the cytotoxic action of certain drugs such as daunorubicin, adriamycin 24,25 and bleomycin. 26 Exposure of cells to ROS has been linked to a variety of physiological and pathological events.…”