Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition

Abstract

Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.

Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia

“…Since HDACi can make chromatin more relaxed, it can enhance cell sensitivity to alkylating agent [28]. We noticed that there are some relevant studies reporting the exciting results of the combination of these two kinds of drugs, exhibiting favorable synergy in vitro [24,29,30]. However, serious hematological toxicity was also observed [17].…”

“…e autophagy-related protein expression also confirmed that the molecular mechanism is through inhibition of Akt/mTOR signaling. Interestingly, vorinostat or bendamustine alone failed to induce autophagy [29,46], thus suggesting that the induction of autophagy is a special trait of NL-101. Generally speaking, Akt needs phosphorylation of threonine phosphorylation site (thr308) or serine phosphorylation site (ser473) to regulate cell's function.…”

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

“…Finally, inhibition of the autophagy (mitophagy), which aggravates the mitochondrial damage and potentiating mitoROS production and mitochondria‐mediated apoptosis, sensitizes ALL to anticancer chemotherapy …”

Quinacrine inhibits GSTA1 activity and induces apoptosis through G1/S arrest and generation of ROS in human non-small cell lung cancer cell lines

“…Inhibition of GSTA1 and ROS generation are two phenomenon's' that are closely connected as GST inhibition results to insufficient dissolution of ROS and enhances the cellular damage by oxidative stress. Few other studies have also pointed out the ROS production effect of quinacrine [44,45], though the mechanism by which it happens is not clearly understood yet. GSTA1 inhibition itself could be a factor in enhancement of ROS due to accumulation of generated nitric oxide, H 2 O 2 and other super oxides.…”