Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Abstract

Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

“…Our findings support the potential of original synthetic Jaspine B analogs in the design of cytotoxic SMS inhibitors that could synergize with classical antitumoral molecules as it was shown for phytosphingosine [13,14].…”

“…Indeed, N-acetylphytosphingosine has been reported to induce apoptosis in human T-cell lymphoma in a mitochondria-dependent manner [12]. Phytosphingosine, another phytosphingolipid, has been shown to enhance the apoptotic response to radiation [13], arsenic [14] or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [15] -resistant cancer cells. These effects are mediated by the activation of several caspases and Bax translocation to the outer leaflet of mitochondria [16] but the impact on ceramide metabolism has never been studied.…”

Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells

“…The increased ROS production induced by comparable low dose of oridonin did not reach the threshold to damage mitochondria leading to apoptosis, but it interrupted tumor intracellular redox status and abrogated the drug resistance of hepatoma cells to As 2 O 3 treatment. Accumulation of excessive ROS in leukemia cells in combined treatment with As 2 O 3 and phytosphingosine led to disruption of the mitochondrial membrane potential, release of apoptotic factors, and resulted in apoptotic cell death (30). In this study, we also provided evidence that the elevation of intracellular ROS level induced by the oridonin-As 2 O 3 combination treatment is essential for the loss of mitochondrial membrane potential and cytochrome C release.…”

“…Numerous reports have demonstrated that combination treatment with As 2 O 3 and other therapeutic agents could sensitize leukaemic or solid cancer cells to As 2 O 3 -induced apoptosis and overcome drug resistance in the treatment of various haematopoietic or solid malignancies (28)(29)(30)(31)(32). The goal of this study was to develop As 2 O 3 -based effective combination therapy against hepato-cellular carcinoma.…”

Induction of apoptosis in human colon cancer HCT-116 cells by anthocyanins through suppression of Akt and activation of p38-MAPK

“…Previous studies demonstrated that p38-MAPK was important in regulating apoptosis by leading to mitochondrial dysfunction which might be related to BAX phophorylation/activation and subsequent translocation to mitochondria (21,22). We previously demonstrated that AIMs induced mitochondrial dysfunction (7).…”