Anti-Myeloma Activity of the Dual Akt/p70S6K Inhibitor EXEL-6075.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 649-649 ◽  
Author(s):  
Douglas W. McMillin ◽  
Joseph M. Negri ◽  
Jake Delmore ◽  
Melissa Ooi ◽  
Patrick Hayden ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Expression Profiles ◽  
Pivotal Role ◽  
In Vivo Studies ◽  
Therapeutic Window ◽  
Ic50 Values

Abstract Context: Akt plays a pivotal role in the survival and proliferation of multiple myeloma (MM) cells and functions as a central link between upstream signaling pathways, such as growth factor receptors (e.g. IL-6/IL-6R, IGF/IGF-1R) and the kinase PI-3K with their downstream signaling effectors, such as the multifunctional mTOR-p70S6K cascade. The pivotal role of Akt in these proliferative/anti-apoptotic cascades for MM has provided the impetus for development of small molecule inhibitors against the kinase activity of Akt. We show that the dual Akt/p70S6K kinase inhibitor EXEL-6075 has potent anti-MM activity in preclinical models. Methods/Results: We tested a panel of 15 human MM cell lines for in vitro response to EXEL-6075 using MTT colorimetric survival assays, which showed that the majority of MM cells responded to EXEL-6075 with IC50 values <0.5 μM, including a subset of 6/15 MM cell lines with IC50 values in the range of 0.1 μM. Importantly, <16 hrs of exposure to 0.5 μM of EXEL-6075 was sufficient to commit these EXEL-6075-sensitive MM cell lines to cell death. Peripheral blood mononuclear cells (PBMCs) remain insensitive to the drug up to 5 μM, consistent with a 1-log therapeutic window compared to the aforementioned sensitive MM cell lines. Other non-malignant tissue, such as bone marrow stromal cells (BMSCs) and immortalized human hepatocyte cells were even less sensitive to EXEL-6075 (IC50>5 μM), further underscoring its selectivity towards neoplastic cells. EXEL-6075-responsive cells included MM cells resistant to diverse conventional and novel agents, such as dexamethasone, bortezomib, and immunomodulatory thalidomide derivatives, suggesting that dual Akt/p70S6K inhibition may overcome mechanisms of constitutive resistance to other currently available therapeutics. EXEL-6075 was also able to overcome the protective effects of IGF-1 and IL-6 on MM.1S cells. In addition, there was modest, if any, protection conferred to MM cells by BMSCs at low drug doses. Interestingly, when we compared the in vitro activity of EXEL-6075 against cell lines from MM vs. other neoplasias (including 11 epithelial cancer cell lines which also exhibited dose-dependent response to this kinase inhibitor), EXEL-6075 was significantly more active against MM cells, as evidenced by the distribution of IC50 values and AUCs of the dose-response curves for each group of cell lines (p=0.028, t-test). Ongoing studies are utilizing gene expression profiles of MM cells highly- vs. moderately-responsive to EXEL-6075, in order to identify putative markers of sensitivity vs. resistance to this kinase inhibitor Conclusion: Targeting the Akt-mTOR-p70S6K pathway is an attractive strategy for the treatment of MM due to the central role Akt plays in proliferation and survival of MM. Inhibition of Akt using the small molecule inhibitor EXEL-6075 resulted in sub-μM killing of MM cell lines with > 1-log differential activity against the non-neoplastic tissues tested in our study. This remains an interesting strategy for the treatment of MM. Future in vivo studies will be needed to confirm these interesting in vitro results.

Anti-Myeloma Activity of the Small-Molecule Aurora Kinase Inhibitor VE465.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3468-3468 ◽  
Author(s):  
Joseph M. Negri ◽  
Douglas W. McMillin ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Therapeutic Window ◽  
Significant Shift ◽  
Aurora Kinase Inhibitor ◽  
Ic50 Values

Abstract Multiple Myeloma (MM) remains an incurable plasma cell neoplasia, despite recent additions in the therapeutic arsenal for its management. Aurora kinases play integral roles in the orchestration of chromosomes and cytoskeletal mobility during the process of cell division. Aurora kinase activity has been implicated in several tumor types, including ovarian, colon, and prostate cancers. To determine whether inhibition of Aurora kinase activity could attenuate myeloma cell survival, we performed studies of the Aurora kinase inhibitor VE465 (Vertex Pharmaceuticals / Merck & Co., Inc.). VE465 inhibits all 3 Aurora isoforms (Aur A, B and C) with approximate Ki values of 1, 26, and 8.7 nM respectively. MTT colormetric survival assays (72–96hrs exposure) showed that VE465 is active against a wide panel of human MM cell lines: 26 of 38 MM cell lines had IC50 values at or < 100 nM, which are significantly lower than IC50 values for normal hematopoietic cells, e.g. unstimulated or PHA-stimatuled PBMCs. Importantly, VE465 was active in vitro against MM cell lines and/or primary MM tumor cells resistant to various anti-MM therapeutics, including dexamethasone, alkylating agents, anthracyclines, the proteasome inhibitor bortezomib, and/or immunomodulatory thalidomide derivatives (IMiDs). Moreover, VE465 maintained its activity despite the presence of protective bone marrow-derived cytokines (e.g. IL-6). PI cell cycle analyses showed that VE465 causes (even within 8 hrs of treatment) caused pronounced G2 arrest, followed by significant shift of MM cells to sub-G1 gate, consistent with cell death. Immunoblotting analyses confirmed that VE465 treatment induces cleavage of PARP, as well as cleavage of caspases-8 and -9, without significant changes in the expression levels of several key molecular effectors (e.g. Mcl-1, Bax, p53, hsp70, hsp90, hs27) which have been previously implicated in the mechanism of anti-MM activity of diverse other therapeutics. Screening of VE465-based combination regimens with other anti-MM agents showed additive effects of VE465 with the histone deacetylase inhibitor Vorinostat (SAHA) (Merck & Co., Inc). Ongoing studies in our Center are addressing the identification of specific molecular markers correlating with the degree of sensitivity of MM cells to VE465. Our in vitro evidence for induction of MM cell death and therapeutic window for the anti-MM effect of VE465, its ability to overcome protective effect of BM-derived cytokines, and the clearly distinct pattern of molecular sequelae of VE465 compared to several other agents in our current anti-MM therapeutic armamentarium, all suggest that Aurora kinase inhibition represents an intriguing novel targeted treatment strategy in MM. Importantly, these studies, particularly the identification of a sizeable subset of MM cell lines with higher sensitivity to VE465 than normal cells, provide the framework for in vivo VE465 studies in progress, alone and in combination with other anti-MM agents, to inform the design of potential clinical trials of this class of agents for MM.

scholarly journals Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

2020 ◽  
Vol 6 (14) ◽  
pp. eaaz9798 ◽  
Author(s):  
Kin Man Au ◽  
Andrew Z. Wang ◽  
Steven I. Park
Keyword(s):  
Small Molecule ◽  
Hodgkin’S Lymphoma ◽  
Kinase Inhibitor ◽  
Drug Carrier ◽  
Hodgkin's Lymphoma ◽  
Therapeutic Window ◽  
Non Hodgkin’S Lymphoma ◽  
Hla Dr ◽  
Non Hodgkin's Lymphoma

Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

CHIR258, a Novel Multi-Targeted Tyrosine Kinase Inhibitor, for the Treatment of t(4;14) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 641-641 ◽  
Author(s):  
Suzanne Trudel ◽  
Zhi Hua Li ◽  
Ellen Wei ◽  
Marion Wiesmann ◽  
Katherine Rendahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Myeloma Cells

Abstract The t(4;14) translocation that occurs uniquely in a subset (15%) of multiple myeloma (MM) patients results in the ectopic expression of the receptor tyrosine kinase, Fibroblast Growth Factor Receptor3 (FGFR3). Wild-type FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoeitic mouse model. The subsequent acquisition of FGFR3 activating mutations in some MM is associated with disease progression and is strongly transforming in several experimental models. The clinical impact of t(4;14) translocations has been demonstrated in several retrospective studies each reporting a marked reduction in overall survival. We have previously shown that inhibition of activated FGFR3 causes morphologic differentiation followed by apoptosis of FGFR3 expressing MM cell lines, validating activated FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these poor-prognosis patients. CHIR258 is a small molecule kinase inhibitor that targets Class III–V RTKs and inhibits FGFR3 with an IC50 of 5 nM in an in vitro kinase assay. Potent anti-tumor and anti-angiogenic activity has been demonstrated in vitro and in vivo. We employed the IL-6 dependent cell line, B9 that has been engineered to express wild-type FGFR3 or active mutants of FGFR3 (Y373C, K650E, G384D and 807C), to screen CHIR258 for activity against FGFR3. CHIR258 differentially inhibited FGF-mediated growth of B9 expressing wild-type and mutant receptors found in MM, with an IC50 of 25 nM and 80 nM respectively as determined by MTT proliferation assay. Growth of these cells could be rescued by IL-6 demonstrating selectivity of CHIR258 for FGFR3. We then confirmed the activity of CHIR258 against FGFR3 expressing myeloma cells. CHIR258 inhibited the viability of FGFR3 expressing KMS11 (Y373C), KMS18 (G384D) and OPM-2 (K650E) cell lines with an IC50 of 100 nM, 250 nM and 80 nM, respectively. Importantly, inhibition with CHIR258 was still observed in the presence of IL-6, a potent growth factors for MM cells. U266 cells, which lack FGFR3 expression, displayed minimal growth inhibition demonstrating that at effective concentrations, CHIR258 exhibits minimal nonspecific cytotoxicity on MM cells. Further characterization of this finding demonstrated that inhibition of cell growth corresponded to G0/G1 cell cycle arrest and dose-dependent inhibition of downstream ERK phosphorylation. In responsive cell lines, CHIR258 induced apoptosis via caspase 3. In vitro combination analysis of CHIR258 and dexamethasone applied simultaneously to KMS11 cells indicated a synergistic interaction. In vivo studies demonstrated that CHIR258 induced tumor regression and inhibited growth of FGFR3 tumors in a plasmacytoma xenograft mouse model. Finally, CHIR258 produced cytotoxic responses in 4/5 primary myeloma samples derived from patients harboring a t(4;14) translocation. These data indicate that the small molecule inhibitor, CHIR258 potently inhibits FGFR3 and has activity against human MM cells setting the stage for a Phase I clinical trial of this compound in t(4;14) myeloma.

In Vitro and In Vivo Activity of the Src/Abl Kinase Inhibitor AP23464 and Analogs Against Activation Loop Mutants of KIT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 793-793 ◽  
Author(s):  
Amie S. Corbin ◽  
Shadmehr Demehri ◽  
Ian J. Griswold ◽  
Chester A. Metcalf ◽  
William C. Shakespeare ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Activation Loop ◽  
Wild Type ◽  
Abl Kinase ◽  
Ic50 Values

Abstract Oncogenic mutations of the KIT receptor tyrosine kinase have been identified in several malignancies including gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM), seminomas/dysgerminomas and acute myelogenous leukemia (AML). Mutations in the regulatory juxtamembrane domain are common in GIST, while mutations in the activation loop of the kinase (most commonly D816V) occur predominantly in SM and at low frequency in AML. Several ATP-competitive kinase inhibitors, including imatinib, are effective against juxtamembrane KIT mutants, however, the D816V mutant is largely resistant to inhibition. We analyzed the sensitivities of cell lines expressing wild type KIT, juxtamembrane mutant KIT (V560G) and activation loop mutant KIT (D816V,F,Y and murine D814Y) to a potent Src/Abl kinase inhibitor, AP23464, and analogs. IC50 values for inhibition of cellular KIT phosphorylation by AP23464 were 5–11 nM for activation loop mutants, 70 nM for the juxtamembrane mutant and 85 nM for wild type KIT. Consistent with this, IC50 values in cell proliferation assays were 3–20 nM for activation loop mutants and 100 nM for wild type KIT and the juxtmembrane mutant. In activation loop mutant-expressing cell lines, AP23464, at concentrations ≤50 nM, induced apoptosis, arrested the cell cycle in G0/G1 and down-regulated phosphorylation of Akt and STAT3, signaling pathways critical for the transforming capacity of mutant KIT. In contrast, 500 nM AP23464 was required to induce equivalent effects in wild-type KIT and juxtamembrane mutant-expressing cell lines. These data demonstrate that activation loop KIT mutants are considerably more sensitive to inhibition by AP23464 than wild type or juxtamembrane mutant KIT. Non-specific toxicity in parental cells occurred only at concentrations above 2 μM. Additionally, at concentrations below 100 nM, AP23464 did not inhibit formation of granulocyte/macrophage and erythrocyte colonies from normal bone marrow, suggesting that therapeutic drug levels would not impact normal hematopoiesis. We also examined in vivo target inhibition in a mouse model. Mice were subcutaneously injected with D814Y-expressing (D816V homologous) murine mastocytoma cells. Once tumors were established, compound was administered three-times daily by oral gavage. One hour post treatment we observed >90% inhibition of KIT phosphorylation in tumor tissue. Following a three-day treatment regimen, there was a statistically significant difference in tumor size compared to controls. Thus, AP23464 analogs effectively target D816-mutant KIT both in vitro and in vivo and inhibit activation loop KIT mutants more potently than the wild type protein. These data provide evidence that this class of kinase inhibitors may have therapeutic potential for D816V-expressing malignancies such as SM or AML.

Anti-Myeloma Activity of Selective PI-3K/PDK/mTOR Inhibitor BEZ235.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1185-1185 ◽  
Author(s):  
Douglas W. McMillin ◽  
Joseph Negri ◽  
Jake Delmore ◽  
Patrick Hayden ◽  
Nicholas Mitsiades ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Single Agent ◽  
In Vivo Studies ◽  
Cross Resistance ◽  
Bone Lesions ◽  
Normal Donor

Abstract Context: The PI3K-Akt-mTOR pathway has been a promising target for the treatment of multiple myeloma (MM). Major cytokine/growth factor receptor cascades (e.g. IGF-1/IGF-1R or IL-6/IL-6R) mediate, at least in part, their proliferative, anti-apoptotic or drug resistance effects through PI3K-Akt-mTOR activation and their downstream effectors. Therefore blocking this signaling pathway at one, or preferably more, of its molecular levels is considered to have promising therapeutic potential for MM. The small molecular mass compound NVP-BEZ235 (Novartis Pharma, Basel Switzerland) allows a multi-targeted, yet selective, inhibition of the PI-3K/Akt/mTOR signaling axis at the level of PI-3K and mTOR and was tested in our pre-clinical MM models. Methods/Results: A panel of human MM cell lines was tested for their in vitro response to NVP-BEZ235 using MTT colorimetric survival assays. All MM cell lines tested exhibited dose- and time-dependent decrease of their viability upon exposure to NVP-BEZ235 (IC50= 25–800 nM for 24–48hrs), without evidence of potential cross-resistance between conventional or novel anti-MM agents and NVP-BEZ235. Indeed, MM cells highly sensitive (IC50 <25 nM) to NVP-BEZ235 (e.g. MM.1S, MM.1R, Dox40 and KMS-12-PE) included both lines known to be sensitive as well as others which are resistant to dexamethasone, cytotoxic chemotherapy, thalidomide and/or its immunomodulatory derivatives (IMIDs). A longitudinal assessment of viability of MM-1S and OPM-2 MM cells during a 48-hr incubation with pharmacologically relevant concentrations of NVP-BEZ235 (25– 400nM) showed rapid commitment to and induction of MM cell death. This result, coupled with the observation that normal donor peripheral blood mononuclear cells (PBMCs) were less sensitive (IC50 >800 nM) than all MM cell lines tested, suggest that this compound exhibits a rapid and tumor-selective effect at clinically relevant conditions. This observation is further supported by our preliminary in vivo studies which suggest anti-MM activity of the drug in a model of diffuse MM bone lesions in SCID/NOD mice. Optimization of dosing and schedule to improve overall survival of NVP-BEZ235 treated mice is ongoing. To provide a more comprehensive framework for possible clinical applications of NVP-BEZ235 for MM treatment, we evaluated a series of combinations of this agent with conventional (e.g. dexamethasone, doxorubicin) and novel (e.g. bortezomib, immunodulatory thalidomide derivatives) anti-MM agents. Given the very potent single-agent activity of NVP-BEZ235 at even low nM concentrations, formal statistical documentation of synergy was not observed, but encouragingly no evidence of antagonism with any of these anti-MM agents was observed, indicating that combinations of NVP-BEZ235 with the aforementioned anti-MM agents can be feasible in clinical settings. Conclusion: The dual PI3K/mTOR inhibitor NVP-BEZ235 induces MM cell killing at sub-μM concentrations, with significantly higher sensitivity of MM cells compared to normal tissues, suggesting that this kinase inhibitor merits further consideration for possible testing as treatment option for MM patients. Further in vitro and in vivo studies are ongoing to further support the translation of these observations to clinical trials in MM.

TG101348: A Dual-Acting JAK2/FLT3 Small Molecule Kinase Inhibitor for the Treatment of AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 898-898
Author(s):  
Betty Tam ◽  
Chi Ching Mak ◽  
Silva Stoughton ◽  
Cyrus Virata ◽  
Dan Lohse ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Complete Regression ◽  
Clinical Prognosis ◽  
Juxtamembrane Region

Abstract A number of genetic mutations have been identified in the development of acute myeloid leukemia (AML), including mutations in the proto-oncogene N-RAS, p53, c-Kit and the FMS-like receptor tyrosine kinase 3 (FLT3). FLT3 plays an important role in the formation of early stem/progenitor cells during hematopoietic development. FLT3 is mutated in ∼30% of AMLs, with internal tandem duplications (ITD) in the juxtamembrane region being the most common (FLT3-ITD). This results in constitutive activation of FLT3 kinase activity and patients harboring such mutations do not respond well to conventional treatments and demonstrate poor clinical prognosis. There is growing evidence that the JAK/STAT pathway may also contribute to the etiology of AML. For instance, the JAK2 V617F point mutation driving various chronic myeloproliferative disorders (MPDs) has recently been detected in de novo AMLs and STAT3/5 phosphorylation is commonly elevated in AML patients. We have developed TG101348, a selective JAK2/FLT3 small molecule inhibitor which has the potential to treat both MPDs and AML. In in vitro based assays, TG101348 was capable of inhibiting the proliferation of human AML cell lines representing a variety of mutations. In AML cell lines carrying mutations in N-RAS such as KG-1, HL-60, and THP-1, EC50s ranged from ∼300 nM-1000 nM. In TF-1a AML cells, which harbor a mutation in p53, TG101348 demonstrated an EC50 of 493 nM. Most interestingly, for these cell lines, FLT3/VEGFR2 specific small molecule inhibitors such SU5416 were significantly less effective, demonstrating EC50s that were generally >10-fold higher. TG101348 was most potent against the FLT3-ITD positive cells lines, MV411 (EC50=57 nM) and MOLM13 (EC50=69 nM). In MV411 cells, TG101348 functionally inhibited FLT3 autophosphorylation, and phosphorylation of downstream intermediates including STAT5, ERK, and AKT. In a human MV411 xenograft models, oral administration (120mg/kg, BID) of TG101348 resulted in complete regression of the subcutaneously implanted MV411 tumors. Taken together, these data suggest that the dual-acting JAK2/FLT3 kinase inhibitor TG101348 may have a therapeutic advantage in that it has the capacity to block multiple pathways critical for dysregulated cell proliferation and survival in AML.

scholarly journals Seaweed Secondary Metabolites In Vitro and In Vivo Anticancer Activity

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 410 ◽  
Author(s):  
Djenisa Rocha ◽  
Ana Seca ◽  
Diana Pinto
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Mode Of Action ◽  
Chemotherapeutic Agents ◽  
In Vivo Studies ◽  
Active Metabolites ◽  
Red Seaweeds ◽  
Ic50 Values

Isolation, finding or discovery of novel anticancer agents is very important for cancer treatment, and seaweeds are one of the largest producers of chemically active metabolites with valuable cytotoxic properties, and therefore can be used as new chemotherapeutic agents or source of inspiration to develop new ones. Identification of the more potent and selective anticancer components isolated from brown, green and red seaweeds, as well as studies of their mode of action is very attractive and constitute a small but relevant progress for pharmacological applications. Several researchers have carried out in vitro and in vivo studies in various cell lines and have disclosed the active metabolites among the terpenoids, including carotenoids, polyphenols and alkaloids that can be found in seaweeds. In this review the type of metabolites and their cytotoxic or antiproliferative effects will be discussed additionally their mode of action, structure-activity relationship and selectivity will also be revealed. The diterpene dictyolactone, the sterol cholest-5-en-3β,7α-diol and the halogenated monoterpene halomon are among the reported compounds, the ones that present sub-micromolar cytotoxicity. Additionally, one dimeric sesquiterpene of the cyclolaurane-type, three bromophenols and one halogenated monoterpene should be emphasized because they exhibit half maximal inhibitory concentration (IC50) values between 1–5 µM against several cell lines.

scholarly journals Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1765-1773 ◽  
Author(s):  
Parvathi Ranganathan ◽  
Xueyan Yu ◽  
Caroline Na ◽  
Ramasamy Santhanam ◽  
Sharon Shacham ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Fold Increase ◽  
In Vivo Studies ◽  
Ic50 Values ◽  
Acute Myeloid

AbstractChromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD–positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.

scholarly journals The Effect of Cucurbit[7]uril on the Antitumor and Immunomodulating Properties of Oxaliplatin and Carboplatin

2021 ◽  
Vol 22 (14) ◽  
pp. 7337
Author(s):  
Ekaterina Pashkina ◽  
Alina Aktanova ◽  
Irina Mirzaeva ◽  
Ekaterina Kovalenko ◽  
Irina Andrienko ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Tumor Cell Lines ◽  
Peripheral Blood Mononuclear ◽  
The Impact

Cucurbit[7]uril (CB[7]) is a molecular container that may form host–guest complexes with platinum(II) anticancer drugs and modulate their efficacy and safety. In this paper, we report our studies of the effect of CB[7]–oxaliplatin complex and the mixture of CB[7] and carboplatin (1:1) on viability and proliferation of a primary cell culture (peripheral blood mononuclear cells), two tumor cell lines (B16 and K562) and their activity in the animal model of melanoma. At the same time, we studied the impact of platinum (II) drugs with CB[7] on T cells and B cells in vitro. Although the stable CB[7]–carboplatin complex was not formed, the presence of cucurbit[7]uril affected the biological properties of carboplatin. In vivo, CB[7] increased the antitumor effect of carboplatin, but, at the same time, increased its acute toxicity. Compared to free oxaliplatin, its complex with CB[7] shows a greater cytotoxic effect on tumor cell lines B16 and K562, while in vivo, the effects of the free drug and encapsulated drug were comparable. However, in vivo studies also demonstrated that the encapsulation of oxaliplatin in CB[7] lowered the toxicity of the drug.

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