Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cδ–dependent mechanisms

Song, Moshi; Gao, Shenmeng; Du, Ke‐Ming; Xu, Min; Yu, Yun; Zhou, Yuhong; Wang, Qiong; Chen, Zhu; Zhu, Yuan‐Shan; Chen, Guoqiang

doi:10.1182/blood-2004-10-4011

Cited by 53 publications

(82 citation statements)

References 53 publications

(51 reference statements)

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“…29,31 Consistent with a recent report, 32 treatment with 32 nM of bortezomib alone induced proteolytic activation of PKCd to a degree (Figure 3a). Dynamic analysis showed that the proteolytic cleavage of PKCd occurred before caspase-3 activation induced by bortezomib (Figure 3b).…”

Section: Pkcd Exerts An Important Role In Bortezomib or Bortezomib Plsupporting

confidence: 79%

“…Mononuclear cells were isolated by Ficoll-Hypaque centrifugation and used for clonogenic assays in methylcellulose as described previously. 29 The cells were cultured in the presence of ATO (1 mM) and/or bortezomib (8 and 16 nM). Colony-forming unit-granulocyte macrophage (CFU-GM) colonies containing at least 50 cells were scored on day 14 on an inverted phase-contrast microscope.…”

Section: Western Blotmentioning

confidence: 99%

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Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

et al. 2007

Leukemia

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Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl þ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 lM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cd (PKCd) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH 2 -terminal kinase and p38. The specific PKCd inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCd plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.

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Section: Pkcd Exerts An Important Role In Bortezomib or Bortezomib Plsupporting

confidence: 79%

Section: Western Blotmentioning

confidence: 99%

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

et al. 2007

Leukemia

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“…Furthermore, PKCd directly interacts with mitochondria and alters mitochondrial function for apoptosis induction (Li et al, 1999). Vice versa, activated caspase-3 has amplifying effect on PKCd activation (Song et al, 2005). Thus, we continued to analyse proteolytic activation of PKCd and caspase-3 as well as the cleavage of poly(ADP ribose) polymerase (PARP), a common substrate of activated caspase-3.…”

Section: Inducible Expression Of Plscr1 Triggers Leukemic Cells To Unmentioning

confidence: 99%

Antileukemic roles of human phospholipid scramblase 1 gene, evidence from inducible PLSCR1-expressing leukemic cells

Huang

Zhao

et al. 2006

Oncogene

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Phospholipid scramblase 1 (PLSCR1) is a multiply palmitoylated protein which is localized in either the cell membrane or nucleus depending on its palmitoylated state. The increasing evidence showed the biological roles of PLSCR1 in cell signaling, maturation and apoptosis. To investigate the functions of PLSCR1 in leukemic cells, we generated an inducible PLSCR1-expressing cell line using myeloid leukemic U937 cells. In this cell line, PLSCR1 was tightly regulated and induced upon tetracycline withdrawal. Our results showed that inducible PLSCR1 expression arrested the proliferation of U937 cells at G 1 phase. Meanwhile, PLSCR1-overexpressing U937 cells also underwent granulocyte-like differentiation with increased sensitivity to etoposide-induced apoptosis. Furthermore, we also found that PLSCR1 induction increased cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 proteins, together with downregulation of S phase kinase-associated protein 2 (SKP2), an F-box subunit of the ubiquitin-ligase complex that targets proteins for degradation. Additionally, PLSCR1 induction significantly decreased c-Myc protein and antiapoptotic Bcl-2 protein. Although the exact mechanism by which PLSCR1 regulates these cellular events and gene expression remains unresolved, our results suggest that PLSCR1 plays the antagonistic role regarding leukemia development. These data will shed new insights into understanding the biochemical and biological functions of PLSCR1 protein.

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“…25 As documented, 15,16 NSC606985 and UV-induced apoptosis is mainly mediated by the intrinsic mitochondrial pathway. To understand if AML1-ETO cleavage also occurs in apoptosis triggered by death receptor, U937-A/E 9/14/18 cells with 48 h AML1-ETO induction were incubated with anti-Fas antibody CH11, which induced caspase-8/3 activation and PKCd cleavage (Figure 2a), indicating the induction of apoptosis.…”

Section: Aml1-eto Protein Is Cleaved Into Four Fragments In Apoptoticmentioning

confidence: 99%

“…12,13 Also, loss of the negative cell cycle regulator p21 WAF1 gene facilitates AML1-ETO-induced leukemogenesis. 14 On the other hand, AML1-ETO endows leukemic cells with susceptibility to apoptosis induced by NSC606985 (a rarely studied camptothecin analog), 15 antiFas antibody, ultraviolent (UV) 16 as well as oridonin (a compound extracted from medicinal herbs). 17 Recently, AML1-ETO protein was also shown to be degraded in apoptosis induced by eriocalyxin B and oridonin.…”

Section: Introductionmentioning

confidence: 99%

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

et al. 2007

Leukemia

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Leukemia-associated fusion protein AML1-ETO is a product of the chromosome translocation (8;21) frequently occurred in acute myeloid leukemia (AML). The fusion oncoprotein blocks leukemic cell differentiation, and it also induces growth arrest with increased sensitivity to apoptosis induction. Such dichotomous functions make it difficult to clarify the role of AML1-ETO in leukemogenesis. Here, we systematically showed that constitutively and overexpressed AML1-ETO protein was cleaved to four fragments of 70, 49, 40 and 25 kDa by activated caspase-3 during apoptosis induction by extrinsic mitochondrial and death receptor signaling pathways. The in vitro proteolytic system combined with MALDI-TOF/TOF mass spectrometer confirmed that AML1-ETO and wild-type ETO but not RUNX1 (AML1) proteins were direct substrates of apoptosis executioner caspase-3. Site-directed mutagenesis analyses identified two nonclassical aspartates (TMPD 188 and LLLD 368 ) as caspase-3-targeted sites in the AML1-ETO sequence. When these two aspartates were mutated into alanines, more intriguingly, the apoptosis-amplified action of AML1-ETO induction completely disappeared, while inducible expression of the caspase-3-cleaved 70 kDa fragment of AML1-ETO after tetracycline removal is sufficient to enhance apoptotic sensitivity. Further investigations on the potential in vivo effects of such a cleavage and its possible role in leukemogenesis would provide new insights for understanding the biology and treatment of AML1-ETO-associated leukemia.

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Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cδ–dependent mechanisms

Abstract: As a promising new class of anticancer drugs, camptothecins have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. In the present study, we report that NSC606985, a rarely studied camptothecin analog, induces apoptosis in acute myeloid leukemia (

Cited by 53 publications

References 53 publications

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Antileukemic roles of human phospholipid scramblase 1 gene, evidence from inducible PLSCR1-expressing leukemic cells

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

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