Biomedical subjects

Zeev Estrov

Publications and source records attributed to Zeev Estrov.

At least 19 recordsLinked to original sources

PubMed2007

Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study.

Following exposure to cytotoxic agents, acute myeloid leukemia (AML) blasts elevate cellular cholesterol in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/ (M2 x day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 x day) by CI, days 4-7] in 15 newly diagnosed and 22 salvage patients with unfavorable (n = 26) or intermediate (n = 10) prognosis cytogenetics. Compared with historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride and total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV + Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe, and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML.

Adult↗

PubMed2007

Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy.

BACKGROUND: Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS: A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS: Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS: Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Adult↗

PubMed2007

Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells.

Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.

Animals↗

PubMed2006

Studying the right cell in acute myelogenous leukemia: dynamic changes of apoptosis and signal transduction pathway protein expression in chemotherapy resistant ex-vivo selected "survivor cells".

We hypothesized that studying protein expression in cells surviving in vitro chemotherapy ("survivor cells", SV), could provide more important insight into the biology of drug-resistant AML cells than analysis of the bulk population of leukemic cells. Leukemia-enriched samples from 79 patients with new or relapsed AML were cultured for four days +/- cytarabine (5-10 microM). Early apoptotic cells were removed to yield purified SV. Expression of BCL2, bax, PKC alpha, ERK2 and pERK2 proteins was measured using laser scanning cytometry. The SV population was enriched for CD34+ stem cells. Protein expression patterns in SV differed considerably from those in controls; culture and reanalysis of protein expression revealed stability, reversion, or new patterns of change. Patterns of pairs or triads of proteins were nonrandomly distributed and appeared at statistically unlikely frequencies, suggesting preferential adoption of certain patterns. The patterns of change were highly predictive of remission attainment, relapse, and survival in univariate and multivariate analysis. We conclude that in vitro SV cells have protein expression patterns distinct from those of the bulk population of leukemic cells and that these patterns are predictive of outcome. Analysis of SV cells may be more informative than analysis of the bulk population of leukemia cells.

Adult↗

PubMed2006

Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.

Acetylation↗

PubMed2006

Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.

Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.

Aged↗

PubMed2006

Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells.

In studies of multiple myeloma cells, atiprimod was shown to block Stat3 activation and inhibited colony-forming cell proliferation. We hypothesized that atiprimod may also inhibit activation of intracellular signaling pathways in AML cells resulting in apoptosis and growth inhibition. We demonstrate that atiprimod inhibited clonogenic growth of AML cell lines and fresh AML marrow cells whereas it did not significantly affect growth of normal hematopoietic progenitors from marrow samples of healthy controls. Atiprimod decreased phosphorylation of Stat3 and Stat5, and protein levels of Jak2, whereas gene expression of Jak2 was not affected. Atiprimod further induced apoptosis by cleavage of caspase 3 and PARP. In summary, our data suggest that atiprimod has a significant antiproliferative and proapoptotic effect on AML cells. This effect may be facilitated by inhibition of the Jak-Stat signaling pathway. Further evaluation of atiprimod in clinical trials of AML should be considered.

Acute Disease↗

PubMed2006

Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia.

Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser(473) and Thr(308); abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34(+) cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC(50) < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2006

Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells.

Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (AML) blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1 but not Bcl-2 and Bcl-X(L) levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8-deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but not the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.

Antineoplastic Agents, Alkylating↗

PubMed2006

Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia.

We investigated the association of plasma thrombopoietin (TPO) and overall survival in 127 patients with previously treated and previously untreated chronic lymphocytic leukemia (CLL). Higher levels of TPO were associated with advanced Rai stage (P < .001), higher levels of beta(2)-microglobulin (beta2-M) (P < .001), and the absence of mutation in the immunoglobulin heavy chain variable region (IgV(H)) (P < .001), and were inversely correlated with platelet count (P = .002). We found that TPO correlated strongly in a continuous manner with overall survival in both previously treated and untreated patients. The univariate Cox proportional hazard model demonstrated that high TPO levels were associated with shorter survival (P < .001), and multiple variable Cox proportional hazards regression analysis demonstrated that this was independent of the IgV(H) mutation status, beta2-M, and Rai stage. Recursive partitioning showed that a cutoff point of 639 pg/mL separated the CLL patients into 2 major survival groups (P < .001). The effects of beta2-M were masked by the effects of TPO in the patients with TPO levels higher than 639 pg/mL, but in the remainder, patients with beta2-M level higher than 4.95 mg/L had significantly shorter survival than those with lower values. Plasma TPO and beta2-M may be useful for the prediction of clinical behavior in CLL and may replace the need for the determination of IgV(H) mutation status.

Adult↗

PubMed2006

Eradication of leukemia stem cells as a new goal of therapy in leukemia.

Leukemias have traditionally been classified and treated on the basis of phenotypic characteristics, such as morphology and cell-surface markers, and, more recently, cytogenetic aberrations. These classification systems are flawed because they do not take into account cellular function. The leukemia cell population is functionally heterogeneous: it consists of leukemia stem cells (LSC) and mature leukemia cells that differentiate abnormally to varying extents. Like normal hematopoietic stem cells, LSCs are quiescent and have self-renewal and clonogenic capacity. Because they are quiescent, LSCs do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and so contribute to treatment failure. These cells may undergo mutations and epigenetic changes, further leading to drug resistance and relapse. Recent data suggest that mature leukemia cells may acquire LSC characteristics, thereby evading chemotherapeutic treatment and sustaining the disease. Ongoing research is likely to reveal the molecular mechanisms responsible for LSC characteristics and lead to novel strategies for eradicating leukemia.

Animals↗

PubMed2006

Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older.

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation.

Acute Disease↗

PubMed2006

Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.

BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.

Animals↗

PubMed2006

Distinct biological impact of dephosphorylation vs. downregulation of p210Bcr-Abl: implications for imatinib mesylate response and resistance.

Imatinib mesylate suppresses phosphorylation of its kinase target, Bcr-Abl. We hypothesized that loss of p210Bcr-Abl (the kinase target) may lead to imatinib mesylate resistance. We studied K562 cells [chronic myelogenous leukemia (CML) blast crisis line] and MO7E/MBA-1 cells (with MBA-1 cells representing MO7E cells stably transfected with BCR-ABL). Imatinib mesylate resistance developed when p210Bcr-Abl expression was abolished. Furthermore, K562 cells were significantly more growth suppressed after imatinib mesylate exposure than after downregulation of Bcr-Abl expression. Signaling pathways which were functional in the absence of Bcr-Abl expression (NF-kappaB and mitogen-activated protein kinase activation or the growth factor pathway) were disrupted when p210Bcr-Abl was present but dephosphorylated, suggesting that an intact, but enzymatically inactive Bcr-Abl, may interfere with critical growth/signaling pathways. Downregulation of p210Bcr-Abl may be a mechanism by which imatinib mesylate resistance emerges. Samples from three of 15 patients with imatinib mesylate-resistant CML blast crisis had undetectable levels of p210Bcr-Abl. We conclude that retention of a dephosphorylated p210Bcr-Abl has a biologic impact distinct from that of downregulation/loss of p210Bcr-Abl and, in a subset of patients, loss of the target of the kinase inhibitor may lead to imatinib mesylate resistance.

Benzamides↗

PubMed2006

Phase II study of low-dose interleukin-11 in patients with myelodysplastic syndrome.

Severe thrombocytopenia places patients with myelodysplastic syndrome (MDS) at risk of serious hemorrhage. Currently, therapeutic options are limited to platelet transfusions. The only commercially available growth factor that increases platelet counts is interleukin-11 (IL-11). We report the results of a phase II trial to more accurately assess the clinical response and toxicity data for low-dose IL-11 (10 microg/kg/day) in patients with MDS. In this study, nine of 32 assessable patients (28%) demonstrated increases in their platelet counts after treatment. Of these, five were considered major platelet responses (15%), as defined by World Health Organization criteria. Four patients had minor platelet responses (13%). The median duration of platelet response was 9 months. Low-dose IL-11 was well tolerated, with no observed grade 4 toxicities. Our study provides additional clinical evidence that chronic administration of IL-11, at low doses, can raise platelet counts and reduce platelet transfusion requirements in a subset of patients with MDS.

Adult↗

PubMed2006

Recombinant human granulocyte-colony-stimulating factor-mobilized and apheresis-collected endothelial progenitor cells: a novel blood cell component for therapeutic vasculogenesis.

BACKGROUND: Endothelial progenitor cells (EPCs) have been identified among hematopoietic tissue-derived progenitor cells that are mobilized into the peripheral blood (PB) as a result of tissue injury. It therefore seems likely that circulating EPCs have therapeutic potential by aiding in the neovascularization of ischemic tissue. This study provides clinical data on the availability of circulating EPCs at steady state and after recombinant human granulocyte-colony-stimulating factor (rHuG-CSF) mobilization and their collection by leukapheresis. STUDY DESIGN AND METHODS: Eight healthy donors underwent rHuG-CSF treatment over 4 days, followed by leukapheresis. Blood samples taken before rHuG-CSF treatment and before apheresis as well as apheresis-collected samples were analyzed by flow cytometry and by real time reverse transcription-polymerase chain reaction for cells expressing EPC-specific surface markers and tissue markers, respectively, and for EPC colony-forming cells. RESULTS: The median PB concentration of CD34+133+ vascular endothelial growth factor receptor-2 (VEGFR-2)-+ EPCs increased 8-fold from steady state to mobilized, and the concentration of CD34+133-VEGFR-2+ EPCs increased by 10-fold. This mobilization pattern was similar to that of hematopoietic CD34+, CD133+, and CD34+117+ progenitor cells. The increase in the median circulating colony-forming unit EPC concentration was 10-fold over baseline. The median absolute number of CD34+133+VEGFR-2+ cells collected by large-volume leukapheresis was 0.8 x 10(6) per kg of body weight. In addition, a small subset of immature CD133+34- cells coexpressing VEGFR-2 was identified in mobilized PB and in the apheresis collection. EPC-specific cells contained in the apheresis product were also identified as expressing mRNA for the CD31 antigen, Tie-2, and VEGFR-2. CONCLUSION: Circulating EPCs represent a novel blood cell component that can be collected by apheresis in large quantities and can be used clinically, either unmanipulated or EPC-selected, for therapeutic vasculogenesis.

Adult↗

PubMed2006

Potential role of activated platelets in homing of human endothelial progenitor cells to subendothelial matrix.

Endothelial progenitor cells (EPCs) mobilize from the bone marrow in response to tissue injury and participate in vascular repair. However, there is limited data about the homing mechanisms of EPCs to vascular injury sites. Recently animal experiments indicated that platelets play a role in recruitment of EPCs to injury sites. However, data on the possible interaction between platelets and EPCs within the human system are limited. We, therefore, examined in-vitro human platelet-EPC interaction under static and flow conditions. Human EPCs were isolated from donated buffy coats by magnetic microbeads and flow cytometry cell sorting using CD133 and VEGFR-2, respectively, as markers. Platelets were tested in the form of washed platelets, platelet rich plasma or whole blood. EPCs formed heterotypic aggregates with resting platelets under static conditions, an interaction that was greatly enhanced when platelets were activated by collagen, ADP or thrombin-activation peptide. The platelet-EPC interaction was inhibited by antibodies to P-selectin or P-selectin glycoprotein ligand-1 (PSGL-1), but not by antibodies to glycoproteins Ib-IX-V or IIb/IIIa. When perfused over activated platelets under shear stress of 2.5 dyn/cm(2), EPCs tethered to platelayers and either adhered immediately or rolled a short distance before adhering. In addition, platelets promoted the colonization of adherent EPCs in culture conditions. Consistent with recent animal studies, these findings demonstrate that human EPCs interact in vitro with activated platelets under static and flow conditions, mediated through P-selectin-PSGL-1 interaction. This interaction may be a central mechanism for homing of EPCs to vascular injury sites.

AC133 Antigen↗

PubMed2005

OSW-1: a natural compound with potent anticancer activity and a novel mechanism of action.

The naturally occurring compound 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-beta-D-xylopyranosyl)-(1-->3)-(2-O-acetyl-alpha-L-arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically significantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40-150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-1 damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration deficiency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fludarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance.

Antineoplastic Agents↗