Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel-induced toxicity in PC-3 and LNCaP prostate cancer cells

Abstract

Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5 mM) and then exposed to various concentrations (0-100 μM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3-methyladenine (5 mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines.

NPRL2 enhances autophagy and the resistance to Everolimus in castration‐resistant prostate cancer

“…With a “defective” autophagy function, NPRL2 silencing CRPC cells treated with Everolimus were prone to apoptosis (Figure E and Figure C). Our data support the notion that inhibition of autophagy sensitizes CRPC cells to ATD therapy, Docetaxel, Salinomycin . Actually, combination of the PI3K/Akt inhibitor and autophagy inhibitors increases their therapeutic effect on PCa .…”

The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells

“…It must be noted that although capsaicin induces an intense ROS increase in the prostate cell line LNCaP, this cell line is less sensitive to the anti-proliferative action of capsaicin as well as to the autophagy blocking. Differences in autophagy induction in both cell lines have been previously found by other authors [ 33 ]. One possible explanation is that autophagy contributes to androgen receptor (AR) degradation in LNCaP cells [ 34 ] and as capsaicin blocks autophagy, AR may be maintained at levels enough to sustain cell proliferation.…”

Autophagy Inhibitor 3-Methyladenine could not Modulate Rotenone Neurotoxicity in Primary Mesencephalic Cell Culture

“…For instance, Stroikin et al (2004) found that treatment of growtharrested human fibroblasts, a classical model of cellular aging, with 3-MA resulted in moderate increase in mitochondria with lowered membrane potential. Pickard et al (2015) showed that 3-MA increased autophagic vesicle formation and apoptotic cell death of LNCaP prostate cancer cells. This toxic effect of 3-MA was reported to be due to blocking of autophagosome formation via the inhibition of class III PI3K with subsequent accumulation of misfolded proteins and altered cell organelles leading to cell damage (Wu et al, 2010).…”