In vitro and in vivo evaluations of the tyrosine kinase inhibitor NSC�680410 against human leukemia and glioblastoma cell lines

Avramis, Ioannis A.; Christodoulopoulos, G.; Suzuki, Atsushi; Laug, Walter E.; González-Gómez, Ignacio; McNamara, George; Sausville, Edward A.; Avramis, Vassilios I.

doi:10.1007/s00280-002-0507-6

Cited by 33 publications

(38 citation statements)

References 18 publications

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“…Recently, adaphostin has been shown to induce apoptosis more rapidly than imatinib mesylate in Bcr/Abl þ cells in conjunction with Bcr/Abl downregulation as well as STAT5 inactivation, and to trigger cell death in imatinib mesylate-resistant cells (Svingen et al, 2000). Subsequently, adaphostin was reported to induce apoptosis in Bcr/Abl À human leukemia lines (e.g., Jurkat, U937), as well as in glioblastoma cells (Avramis et al, 2002). In a very recent communication, Chandra et al (2003) observed that adaphostin induced apoptosis in various human leukemia cell lines in association with generation of reactive oxygen species.…”

Section: Introductionmentioning

confidence: 96%

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Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process

Rahmani

Almenara

et al. 2003

Oncogene

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Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations X0.75 lM for intervals X6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-Nterminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2-and CDK4-specific sites, as well as the caspasedependent downregulation of cyclin D 1 . Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/ MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/ MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.

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Section: Introductionmentioning

confidence: 96%

“…trigger apoptosis in several Bcr/Abl À human leukemia cell types (Avramis et al, 2002). Moreover, very recent results suggest that adaphostin induces apoptosis through an oxidative stress-related mechanism (Chandra et al, 2003).…”

Section: Induction Of Apoptosis In Human Leukemia Cells By Tyrosine Kmentioning

confidence: 99%

Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process

Rahmani

Almenara

et al. 2003

Oncogene

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“…37 Briefly, cells (8 3 10 3 cells/well) were seeded into 96-well plates and, after 24 hours, exposed to the agents under study. After treatment, the medium was replaced with 100 mL of MTT solution (0.5 mg/mL in cell culture medium) and incubated at 37°C for 2 hours.…”

Section: Micrococcal Nuclease Digestion-based Analysis Of Chromatin Cmentioning

confidence: 99%

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Γκοτζαμανίδου

Terpos

Bamia

et al. 2016

Blood

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Key Points• Responders to melphalan therapy are characterized by slower rates of NER and DSB/R mechanisms and higher apoptotic rates.• The DSB/R inhibitor SCR7 enhances cytotoxicity of melphalan against myeloma plasma cells.DNA repair activity of malignant cells seems to influence therapeutic outcome and patients' survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n 5 17) or did not respond (n 5 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders' BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders' cells compared with those of nonresponders (P 5 .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates of DSB/R and increased melphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders' BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. (Blood. 2016;128(9):1214-1225

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“…21 Moreover, rather than antagonizing protein degradation, the combination of the proteasome inhibitor, bortezomib, with adaphostin was found to enhance downregulation of Raf-1. 26 Inhibition of protein synthesis by adaphostin has been demonstrated in human T-lymphoblastic leukaemia cell lines, 20 but this would not account for the sudden loss of stability of pre-existing proteins that we observed for adaphostin-treated cells. It has also been reported that the prototypical tyrphostin, AG957, effectively depletes p210 Bcr-Abl by covalently crosslinking it into higher molecular weight complexes, 27 but it is unclear whether adaphostin shares this property.…”

Section: Discussionmentioning

confidence: 83%

“…18,19 In contrast to imatinib, which rapidly abolishes tyrosine kinase activity and induces apoptosis gradually in the CML cell line K562, adaphostin induces rapid apoptosis and inhibits tyrosine phosphorylation more slowly. 18 Moreover, adaphostin has been reported to induce cell death in cell lines that do not express Bcr-Abl, including T-cell lymphoblastic leukaemia cells (Jurkat and CEM) 18,20,21 and murine myeloid cell lines such as FDC-P1 18 and Ba/F3. 10 Paradoxically, adaphostin does not exhibit selectivity for murine cell lines transformed with Bcr-Abl but does cause selective growth inhibition of CML granulocyte colony-forming units relative to normal progenitors.…”

Section: Introductionmentioning

confidence: 99%

Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

Barnes

Hensbergen

et al. 2007

Leukemia

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In vitro and in vivo evaluations of the tyrosine kinase inhibitor NSC�680410 against human leukemia and glioblastoma cell lines

Cited by 33 publications

References 18 publications

Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process

Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

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