scholarly journals Παθολογική φυσιολογία οστικών μετασταστάσεων στους καρκίνους του μαστού και του προστάτη σε in vivo μοντέλα μυών

2012 ◽  
Author(s):  
Παναγιώτης Δαλέζης
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Bone Lesions ◽  
Osteolytic Lesions ◽  
Treatment Scheme ◽  
Anticancer Effects ◽  
4T1 Cells ◽  
Agent Treatment

Pathophysiology of Bone metastases in breast and prostate cancerwith the aid of in vivo mice models; Effect of hormonal analoguesBone metastases are a frequent compilation of cancer, occurringin up to 70 percent of patients with advanced breast and prostate cancer.An extensive line of research has documented that bones constitutes afavorable microenvironment for homing prostate and breast cancercells. Metastases can be osteoblastic, osteolytic, or mixed; they resultfrom increased osteoclastic activity due to an imbalance betweenRANK ligand expression and OPG expression. In breast cancer,osteolytic lesions are most common, whereas in prostate cancer,osteoblastic lesions predominate. In the present work we tested:• The anticancer effects of dexamethasone (DEX), octreotide(OCT), docetaxel (DOC) and their combination on the TRAMP-C1prostate cancer model, in vitro and in vivo.• The anticancer effects of DEX, OCT, adriamycin (ADR) andtheir combination on 4T1 breast cancer model, in vitro and in vivo.• TRAMP-C1 and 4T1 cells were first characterized forsomatostatin receptors (SSTR 1-5) expression and then inoculated ontothe femur of C57Bl and BALB/c mice, respectively. Investigationprotocols included TRAMP-C1 and 4T1 cell proliferation, migrationand invasion assays, in vitro, and the analysis of radiographic images ofbone lesions and the survival of diseased animals.We documented that:• The TRAMP-C1 cells express the SSTR-1, -2, -3 and -5 and arecapable of producing osteoblastic lesions onto the femur of C57Blmice. DEX, OCT and DOC exerted significant anticancer effects onTRAMP-C1 cell proliferation, invasion and migration assays, in vitro.The triple combination treatment scheme (DEX-OCT-DOC) showed asignificant synergistic/additive anticancer effects, reducing by 5-foldthe dose of DOC required for maximal anticancer effects, in vitro. Inaddition, the triple combination regimen produced significantanticancer effects on TRAMP-C1 cell invasion assays better than anysingle agent treatment scheme, with the exception of DEX, whichproduced the maximal inhibitory effect on TRAMP-C1 cell invasionassay. Furthermore, DEX and OCT, when administered as single orcombination treatment schemes did not produce significant anticancereffects on the overall survival of the diseased animals, according to thecriteria established by NCI [Treated animals vs Controls (T/C >125%)].DOC produced a significant anticancer effect, which reflected to theshrinkage of the bone lesions and to a significant increase of the overallsurvival of diseased animals (T/C = 133%), however, the administration of DEX plus OCT regimen prior to DOC therapysignificantly improved the DOC anticancer effects on bone lesions andoverall survival (T/C = 150%). This data suggest that neoadjuvantadministration of DEX plus OCT regimen can improve the anticanceractions of DOC on TRAM-C1 prostate cancer models in vitro and invivo.• The 4T1 cells express the SSTR-2, -3, -4 and -5 and are capableof producing osteolytic lesions onto the femur of BALB/c mice. OCTand DEX induce a dose dependent cell death in vitro. When OCTcombined with DEX showed an antagonistic effect on 4T1 cell line.The combination of OCT plus DEX was ineffective on growthinhibition. The combination of OCT and DEX with ADR had also anantagonistic effect in 4T1 cell line. On the other hand, the singletreatment schemes revealed that the invasion capacity of 4T1 cells wasinhibited by 26% using DEX, by 15% using OCT, and increased by13.2% using ADR single- agent treatment schemes. However, the triplecombination treatment scheme resulted in stimulation by 37.3% of the4T1 cell invasion capability.OCT does not result in significant increase of lifespan of the 4T1 bearing mice, as a single agent (T/C = 105.3%). When we treated 4T1breast cancer bearing mice with DEX and DEX plus OCT, theirmedium survival time (MST) was reduced (T/C= 97.4 % and 94.7 %respectively) to the MST of the untreated animal group (controlT/C=100%). On the other hand, when ADR was used alone, asignificant increase to the lifespan of the mice (T/C = 144.7 %).However, when all three drugs were used in combination, the antitumoractivity of ADR was neutralized (T/C = 110.5%). Also, the animalstreated with combination of the drugs developed more extensiveosteolytic bone destruction than the untreated animals or the animalstreated with one drug alone. This data indicated that the combination ofOCT with DEX in the treatment of 4T1 mouse breast cancer isineffective. The simultaneous use of these drugs should be carefullyconsidered because they also neutralized the antitumor activity of theADR.

scholarly journals Selective Targeting of Breast Cancer by Tafuramycin a Using SMA-Nanoassemblies

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3532
Author(s):  
Ibrahim M. El-Deeb ◽  
Valeria Pittala ◽  
Diab Eltayeb ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptors ◽  
In Vivo Studies ◽  
Chemotherapy Agent ◽  
Anticancer Effects ◽  
Tumor Tissues ◽  
Potential Strategy ◽  
Tumor Accumulation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals Ethyl Acetate Fraction from Hedyotis diffusa plus Scutellaria barbata Exerts Anti-Breast Cancer Effect via miR-200c-PDE7B/PD-L1-AKT/MAPK Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yue Yang ◽  
Ting Fang ◽  
Yi-Lan Cao ◽  
Ya-Xin Lv ◽  
Qing-Qi Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ethyl Acetate ◽  
Colony Formation ◽  
Ethyl Acetate Fraction ◽  
Aqueous Extracts ◽  
Optimal Ratio ◽  
Hedyotis Diffusa ◽  
4T1 Cells

Background. Hedyotis diffusa (HD) Willd. and Scutellaria barbata (SB) D. Don in different ratios have been frequently used to treat various cancers in clinical Traditional Chinese Medicine prescriptions. However, the optimal ratio, active fraction, and molecular mechanisms associated with the anti-breast cancer role of this herbal couplet have not been elaborated. Methods. To screen out the optimal ratio of this herbal couplet, we compare aqueous extracts of HD, SB, or HD plus SB in different weight ratios (HS11, HS12, HS21) for their anticancer effects on murine breast cancer 4T1 cells in vitro and in vivo. EA11, the ethyl acetate fraction from HS11 (the aqueous extract of the couplet at an equal weight ratio), is further assessed for its antiproliferative effect as well as the antitumorigenic impact with the aid of immunocompetent mice. Colony formation, flow cytometry, western blot, ELISA, and qRT-PCR are used to elucidate mechanisms underlying EA11-led effects. Results. HS11 presents the most potential suppression of 4T1 cell proliferation and tumor growth among these aqueous extracts. The comparison results show that EA11 is more effective than HS11 in vitro and in vivo. EA11 inhibits colony formation and induces apoptosis in a concentration-dependent manner. EA11 reduces the protein expressions of PDE7B, PD-L1, β-catenin, and cyclin D1 while elevating the concentration of cellular cAMP and miR-200c expression in 4T1 cells. Additionally, EA11 exerts its anticancer effect partially via the inactivation of MAPK and AKT signaling pathways. Conclusions. This study implicates that EA11 prevents breast tumor development by interfering with the miR-200c-PDE7B/PD-L1-AKT/MAPK axis. EA11 may represent a potential therapeutic candidate for breast cancer.

Combination of the glycoengineered Type II CD20 antibody obinutuzumab (GA101) and The novel Bcl-2 selective Inhibitor GDC-0199 Results in superior In Vitro and In Vivo Anti-tumor activity in models Of B-Cell Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4412-4412 ◽  
Author(s):  
Deepak Sampath ◽  
Sylvia Herter ◽  
Frank Herting ◽  
Ellen Ingalla ◽  
Michelle Nannini ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Employment Equity ◽  
Direct Cell ◽  
Xenograft Models ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Agent Treatment

Introduction Obinutuzumab (GA101) is a novel glycoengineered type II, anti-CD20 monoclonal antibody induces a high level of direct cell death. As a result of glycoengineering, GA101 has increased affinity for FcgRIIIa on effector cells resulting in enhanced direct cell death and ADCC induction. GA101 is currently in pivotal clinical trials in CLL, indolent NHL and DLCBL. ABT-199 (GDC-0199) is a novel, orally bioavailable, selective Bcl-2 inhibitor that induces robust apoptosis in preclinical models of hematological malignancies and is currently in clinical trials for CLL, NHL and MM. Based on their complementary mechanisms of action involving increased apoptosis (GDC-0199) or direct cell death (GA101) the combination of anti-CD20 therapy with a Bcl-2 inhibitor has the potential for greater efficacy in treating B lymphoid malignancies. Experimental Methods The combination of GA101 or rituximab with GDC-0199 was studied in vitro utilizing assays that measure direct cell death induction/apoptosis (AxV/Pi positivity) on WSU-DLCL2, SU-DHL4 DLBCL and Z138 MCL cells by FACS and the impact of Bcl-2 inhibition on ADCC induction. In vivo efficacy of the combination of GA101 or rituximab and GDC-0199 was evaluated in SU-DHL4 and Z138 xenograft models. Results GA101 and rituximab enhanced cell death induction when combined with GDC-0199 in SU-DHL4, WSU-DLCL2 and Z138 cell lines. When combined at optimal doses an additive effect of the two drugs was observed. GDC-0199 did not negatively impact the capability of GA101 or rituximab to induce NK-cell mediated ADCC. Combination of GDC-0199 and GA101 induced a greater than additive anti-tumor effects in the SU-DHL4 and Z138 xenograft models resulting in tumor regressions and delay in tumor regrowth when compared to monotherapy. Moreover, continued single-agent treatment with GDC-0199 after combination with GA101 resulted in sustained in vivo efficacy in the SU-DHL4 model. Conclusions Our data demonstrate that the combination of GA101 with GDC-0199 results in enhanced cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types that is comparable to the combination of rituximab with GDC-0199. In addition, single-agent treatment with GDC-0199 following combination with GA101 sustains efficacy in vivo suggesting a potential benefit in continued maintenance therapy with GDC-0199. Collectively the preclinical data presented here supports clinical investigation of GA101 and GDC-0199 combination therapy, which is currently in a phase Ib clinical trial (clinical trial.gov identifier NCT01685892). Disclosures: Sampath: Genentech: Employment, Equity Ownership. Herter:Roche: Employment. Herting:Roche: Employment. Ingalla:Genentech: Employment. Nannini:Genentech: Employment. Bacac:Roche: Employment. Fairbrother:Genentech: Employment, Equity Ownership. Klein:Roche Glycart AG: Employment.

scholarly journals Galectin-3 Regulates the Expression of Tumor Glycosaminoglycans and Increases the Metastatic Potential of Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathas Xavier Pereira ◽  
Sofia Nascimento dos Santos ◽  
Thaís Canuto Pereira ◽  
Mariana Cabanel ◽  
Roger Chammas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Cancer Progression ◽  
Metastatic Potential ◽  
Migration Ability ◽  
Tumor Cell Migration ◽  
Galectin 3 ◽  
4T1 Cells

Galectin-3 (Gal-3) is a multifunctional β-galactoside-binding lectin that once synthesized is expressed in the nucleus, cytoplasm, cell surface, and extracellular environment. Gal-3 plays an important role in breast cancer tumors due to its ability to promote interactions between cell-cell and cell-extracellular matrix (ECM) elements, increasing tumor survival and metastatic dissemination. Still, the mechanism by which Gal-3 interferes with tumor cell migration and metastasis formation is complex and not fully understood. Here, we showed that Gal-3 knockdown increased the migration ability of 4T1 murine breast cancer cells in vitro. Using the 4T1 orthotopic breast cancer spontaneous metastasis mouse model, we demonstrated that 4T1-derived tumors were significantly larger in the presence of Gal-3 (scramble) in comparison with Gal-3 knockdown 4T1-derived tumors. Nevertheless, Gal-3 knockdown 4T1 cells were outnumbered in the bone marrow in comparison with scramble 4T1 cells. Finally, we reported here a decrease in the content of cell-surface syndecan-1 and an increase in the levels of chondroitin sulfate proteoglycans such as versican in Gal-3 knockdown 4T1 cells both in vitro and in vivo. Overall, our findings establish that Gal-3 downregulation during breast cancer progression regulates cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycans (PG), thus enhancing the metastatic potential of tumor cells.

scholarly journals Dark Sweet Cherry (Prunus avium) Anthocyanins Inhibited the Growth and Biomarkers for Breast Cancer Growth and Invasion in Highly Metastatic 4T1 Tumor Cells

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 279-279
Author(s):  
Ana Carolina Silveira Rabelo ◽  
Shirley Arbizu ◽  
Maria Angelica Miglino ◽  
Susanne Talcott ◽  
Giuliana Noratto
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Viability ◽  
Prunus Avium ◽  
Epithelial Mesenchymal Transition ◽  
Dose Range ◽  
Mesenchymal Transition ◽  
4T1 Cells

Abstract Objectives To investigate the mechanisms underlying the breast cancer anti-invasive activity of DSC phenolics enriched in anthocyanins (ACN) in vitro and their potential in vivo. Methods 4T1 cells were treated with ACN extracted from DSC concentrate juice (FruitSmart, Grandview, WA) within dose range 20–80 µg cyanidin 3-glucoside equivalent (C3G)/mL to assess reactive oxygen species (ROS) levels using carboxy-H2DFFDA probe and cell viability using the resazurin kit (Sigma-Aldrich, St Louis, MO). Protein and mRNA expression were investigated using standard procedures and cell migration by wound healing assay. The pilot in vivo study was performed with 4T1 cells orthotopically injected into mammary fat pads of BALB/c mice (Envigo, Houston, TX, USA) (n = 4). After tumor growth, animals were gavaged with ACN (150 mg C3G/kg body weight/day, n = 2) or saline solution (control, n = 2) for one week followed by euthanasia and collection of tumors, lungs, and liver tissues for analyses. Results ACN induced ROS production (up to 5.13-fold of control) and inhibited cell viability by 50% (IC50) at 58.6 µg C3G/mL. The ACN (IC50 dose) treatment downregulated phospho-ERK1/2 and upregulated phospho-p38 proteins, linked to cell growth inhibition and caspase-dependent apoptosis mediated by the increase in cleaved/total caspase-3 protein ratio (∼3-fold of control) and suppression of total PARP (∼0.4-fold of control). ACN also suppressed the Akt/mTOR/CREB pathway that promotes proliferation and invasion. 4T1 cell migration was inhibited by 22%, consistent with the phospho-Src downregulation (down to ∼ 0.25-fold of control), that regulate epithelial-mesenchymal transition. Phospho-ERK1/2 and phospho-CREB were downregulated in mice tumors. This was accompanied by the downregulation of Cenpf mRNA in liver and lungs, which correlates with poor prognosis and metastasis, thus supporting the in vitro findings. Conclusions ACN provides a dietary alternative to fight human breast cancer invasion by incorporating DSC into the diet. More studies are guarantee to help improve the quality of life of breast cancer patients. Funding Sources This work was supported by the Northwest Cherry Growers. The authors thank the support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Brazil for providing Ana Carolina Silveira Rabelo the scholarship.

Self-assembled tocopherol-albumin nanoparticles with full biocompatibility for chemo-photothermal therapy against breast cancer

2021 ◽  
Vol 19 ◽  
Author(s):  
Haijun Shen ◽  
Qianqian Gao ◽  
Tingting Liu ◽  
Haoran Wang ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photothermal Therapy ◽  
Normal Liver ◽  
Laser Exposure ◽  
Multifunctional Nanoparticle ◽  
Self Assembled ◽  
4T1 Cells ◽  
Biocompatible Nanoparticle

Background:: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications. Objective: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials. Methods: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated. Results: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo. Conclusion: The self-assembled HIT-NPs could provide a promising platform for combined chemo-photothermal cancer therapy with full biocompatibility.

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.

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