Abstract
Reveratrol, a plant antibiotic, has been found anticancer activity and was recently reported to induce apoptosis in the myeloid leukemia line HL60 by the CD95-CD95 ligand pathway. However, many acute lymphoblastic leukemias (ALLs), particularly of B-lineage, are resistant to CD95-mediated apoptosis. Using leukemia lines derived from patients with pro-B t(4;11), pre-B, and T-cell ALL, we show in this report that resveratrol induces extensive apoptotic cell death not only in CD95sensitive leukemia lines, but also in B-lineage leukemic cells that are resistant to CD95-signaling. Multiple dose treatments of the leukemic cells with 50 μM resveratrol resulted in ≥80% cell death with no statistically significant cytotoxicity against normal peripheral blood mononuclear cells under identical conditions. Resveratrol treatment did not increase CD95 expression or trigger sensitivity to CD95-mediated apoptosis in the ALL lines. Inhibition of CD95-signaling with a CD95-specific antagonistic antibody indicated that CD95-CD95 ligand interactions were not involved in initiating resveratrol-induced apoptosis. However, in each ALL line, resveratrol induced progressive loss of mitochondrial membrane potential as measured by the dual emission pattern of the mitochondria-selective dye JC-1. The broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala Asp-fluoromethylketone failed to block the depolarization of mitochondrial membranes induced by resveratrol, further indicating that resveratrol action was independent of upstream caspase-8 activation via receptor ligation. However, increases in caspase-9 activity ranged from 4- to 9-fold in the eight cell lines after treatment with resveratrol. Taken together, these results point to a general mechanism of apoptosis induction by resveratrol in ALL cells that involves a mitochondria/caspase-9-specific pathway for the activation of the caspase cascade and is independent of CD95-signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4731-4739 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 61 |
| Issue number | 12 |
| State | Published - Jun 15 2001 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. / Dörrie, J.; Gerauer, H.; Wachter, Y.; Zunino, S. J.
In: Cancer Research, Vol. 61, No. 12, 15.06.2001, p. 4731-4739.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells
AU - Dörrie, J.
AU - Gerauer, H.
AU - Wachter, Y.
AU - Zunino, S. J.
PY - 2001/6/15
Y1 - 2001/6/15
N2 - Reveratrol, a plant antibiotic, has been found anticancer activity and was recently reported to induce apoptosis in the myeloid leukemia line HL60 by the CD95-CD95 ligand pathway. However, many acute lymphoblastic leukemias (ALLs), particularly of B-lineage, are resistant to CD95-mediated apoptosis. Using leukemia lines derived from patients with pro-B t(4;11), pre-B, and T-cell ALL, we show in this report that resveratrol induces extensive apoptotic cell death not only in CD95sensitive leukemia lines, but also in B-lineage leukemic cells that are resistant to CD95-signaling. Multiple dose treatments of the leukemic cells with 50 μM resveratrol resulted in ≥80% cell death with no statistically significant cytotoxicity against normal peripheral blood mononuclear cells under identical conditions. Resveratrol treatment did not increase CD95 expression or trigger sensitivity to CD95-mediated apoptosis in the ALL lines. Inhibition of CD95-signaling with a CD95-specific antagonistic antibody indicated that CD95-CD95 ligand interactions were not involved in initiating resveratrol-induced apoptosis. However, in each ALL line, resveratrol induced progressive loss of mitochondrial membrane potential as measured by the dual emission pattern of the mitochondria-selective dye JC-1. The broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala Asp-fluoromethylketone failed to block the depolarization of mitochondrial membranes induced by resveratrol, further indicating that resveratrol action was independent of upstream caspase-8 activation via receptor ligation. However, increases in caspase-9 activity ranged from 4- to 9-fold in the eight cell lines after treatment with resveratrol. Taken together, these results point to a general mechanism of apoptosis induction by resveratrol in ALL cells that involves a mitochondria/caspase-9-specific pathway for the activation of the caspase cascade and is independent of CD95-signaling.
AB - Reveratrol, a plant antibiotic, has been found anticancer activity and was recently reported to induce apoptosis in the myeloid leukemia line HL60 by the CD95-CD95 ligand pathway. However, many acute lymphoblastic leukemias (ALLs), particularly of B-lineage, are resistant to CD95-mediated apoptosis. Using leukemia lines derived from patients with pro-B t(4;11), pre-B, and T-cell ALL, we show in this report that resveratrol induces extensive apoptotic cell death not only in CD95sensitive leukemia lines, but also in B-lineage leukemic cells that are resistant to CD95-signaling. Multiple dose treatments of the leukemic cells with 50 μM resveratrol resulted in ≥80% cell death with no statistically significant cytotoxicity against normal peripheral blood mononuclear cells under identical conditions. Resveratrol treatment did not increase CD95 expression or trigger sensitivity to CD95-mediated apoptosis in the ALL lines. Inhibition of CD95-signaling with a CD95-specific antagonistic antibody indicated that CD95-CD95 ligand interactions were not involved in initiating resveratrol-induced apoptosis. However, in each ALL line, resveratrol induced progressive loss of mitochondrial membrane potential as measured by the dual emission pattern of the mitochondria-selective dye JC-1. The broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala Asp-fluoromethylketone failed to block the depolarization of mitochondrial membranes induced by resveratrol, further indicating that resveratrol action was independent of upstream caspase-8 activation via receptor ligation. However, increases in caspase-9 activity ranged from 4- to 9-fold in the eight cell lines after treatment with resveratrol. Taken together, these results point to a general mechanism of apoptosis induction by resveratrol in ALL cells that involves a mitochondria/caspase-9-specific pathway for the activation of the caspase cascade and is independent of CD95-signaling.
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M3 - Article
VL - 61
SP - 4731
EP - 4739
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 12
ER -