Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Abstract

Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

A specific combination of zeaxanthin, spermidine and rutin prevents apoptosis in human dermal papilla cells

“…The anti-apoptotic action of the compounds is likely due to suppression of caspase-3 expression, preservation of phosphorylated Akt and ERK, and counteraction of Bcl-2 loss. Previously, it was shown that flavonoids with a chemical structure similar to rutin exerted anti-apoptotic actions by blocking the activity of caspase-3 (22)(23)(24)(25), zeaxanthin could reduce the extent of nuclear fragmentation and typical apoptotic events in photoreceptors (26), and polyamines may be involved in promotion of hair growth (27)(28)(29). Taken together, these data may explain the greater protective effects that our compounds exhibited in combination rather than as single agents.…”

Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity

“…For instance, Caov-3 cells that carry a point mutation leading to expression of an abnormal transcript encoding an inactive p53 [ 31 , 32 ], and SK-OV-3 cells that carry a single nucleotide deletion in the p53 gene and are not able to generate a p53 transcript [ 31 , 33 , 56 , 57 ], both have defects in their apoptotic machinery that associates with resistance to standard platinum therapy [ 58 - 60 ]. Conversely, OV2008 and A2780 cells expressing wild type p53 are very sensitive to cytotoxic drugs such as cisplatin [ 14 , 25 ], paclitaxel [ 61 , 62 ], or doxorubicin [ 63 - 65 ], rapidly undergoing apoptosis. Our data demonstrate that mifepristone, at concentrations beyond those used to achieve cytostasis has lethal activity triggering a caspase-associated apoptotic process in all six ovarian cancer cell lines studied regardless of their p53 genetic backgrounds and sensitivities to cisplatin.…”

Inhibition of apoptosis by progesterone in cardiomyocytes

“…In addition to inducing oxidative stress, Dox at high concentrations can interact with DNA topoisomerase and cause DNA strand breaks (Gewirtz 1999). At the cellular level, Dox has often been used as a model compound for inducing apoptosis in a number of experimental systems including cardiomyocytes (Kumar et al 1999; Arola et al 2000; Kalyanaraman et al 2002; Ueno et al 2006; Bruynzeel et al 2007). …”