In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery

AbstractAmong various homing devices, peptides containing the NGR tripeptide sequence represent a promising approach to selectively recognize CD13 receptor isoforms on the surface of tumor cells. They have been successfully used for the delivery of various chemotherapeutic drugs to tumor vessels. Here, we report on the murine plasma stability, in vitro and in vivo antitumor activity of our recently described bioconjugates containing daunorubicin as payload. Furthermore, CD13 expression of KS Kaposi’s Sarcoma cell line and HT-29 human colon carcinoma cell line was investigated. Flow cytometry studies confirm the fast cellular uptake resulting in the rapid delivery of the active metabolite Dau = Aoa-Gly-OH to tumor cells. The increased in vitro antitumor effect might be explained by the faster rearrangement from NGR to isoDGR in case of conjugate 2 (Dau = Aoa-GFLGK(c[NleNGRE]-GG)-NH2) in comparison with conjugate 1 (Dau = Aoa-GFLGK(c[KNGRE]-GG)-NH2). Nevertheless, results indicated that both conjugates showed significant effect on inhibition of proliferation in the primary tumor and also on blood vessel formation making them a potential candidate for targeting angiogenesis processes in tumors where CD13 and integrins are involved.

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The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo

Blood ◽

10.1182/blood-2010-01-265769 ◽

2010 ◽

Vol 116 (22) ◽

pp. 4578-4587 ◽

Cited By ~ 189

Author(s):

Victoria J. Weston ◽

Ceri E. Oldreive ◽

Anna Skowronska ◽

David G. Oscier ◽

Guy Pratt ◽

...

Keyword(s):

Cell Line ◽

Tumor Cells ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Prolymphocytic Leukemia ◽

Dna Double Strand Break ◽

Break Repair

Abstract The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

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Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽

10.1182/blood-2019-126298 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1844-1844

Author(s):

John Richards ◽

Myriam N Bouchlaka ◽

Robyn J Puro ◽

Ben J Capoccia ◽

Ronald R Hiebsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Tumor Growth Inhibition ◽

Employment Equity ◽

Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

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Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (−)-gossypol

Asian Journal of Andrology ◽

10.1038/aja.2009.87 ◽

2010 ◽

Vol 12 (3) ◽

pp. 390-399 ◽

Cited By ~ 21

Author(s):

Xian-Qing Zhang ◽

Xiao-Feng Huang ◽

Shi-Jie Mu ◽

Qun-Xing An ◽

Ai-Jun Xia ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Line ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Inhibition Of Proliferation

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Ectonucleosidase CD39 Is Highly Expressed on ATLL Cells and Suppresses the Immune Response through the Adenosine Pathway

Blood ◽

10.1182/blood-2018-99-118555 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3720-3720

Author(s):

Yasuhiro Nagate ◽

Sachiko Ezoe ◽

Jiro Fujita ◽

Takafumi Yokota ◽

Michiko Ichii ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Line ◽

Tumor Cells ◽

Research Funding ◽

Poly I:C ◽

Acute Type ◽

Atll Cell

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, linked to the human T-cell lymphotropic virus, HTLV-1. Patients with ATLL are often at the risk of opportunistic infections. Some studies suggested that ATLL cells originate from HTLV-1-infected regulatory T cells (Tregs). It could be possible that this immunocompromised state is caused by the function of ATLL cells having similar phenotypes with Tregs. In this study, we examined the expression of immunosuppressive molecules associated with Tregs in ATLL cells, and analyzed their roles in the function of ATLL cells. Methods: The protocol of this study was approved by the Investigational Review Board of Osaka University Hospital. Peripheral blood mononuclear cells (PBMCs) were collected from 10 asymptomatic HTLV-1 carriers and 22 ATLL patients (1 with smoldering type, 5 with chronic type, 2 with lymphoma type, and 14 with acute type) after getting informed consent. PBMCs from 3 ATLL patients were separated into CD4+ CD7- CADM1+ATLL cells and adjacent CD4+CD7+ CADM1-normal T cells using Fluorescence-activated Cell Sorter (FACS), and cells in each fraction were subjected to total RNA sequencing experiments. Based on the results, we examined the expression patterns of CD39 and CD73 in HTLV-1 carriers or each type of ATLL patients, and also analyzed the immune functions of these molecules in ATLL tumor cells. Results: We compared whole transcriptome of ATLL cells and normal CD4+cells. Bioinformatic analyses showed that many genes associated with immunosuppressive functions were elevated or downregulated in ATLL cells. Among these genes we focused on CD39, CD73 and CD26, because they have recently been reported to be strongly associated with the functions of Tregs. CD39, expressed on normal Tregs, and extrinsic CD73 have immunosuppressive potential by catalyzing adenosine from extracellular ATP, and CD26 has opposite potential by resolving adenosine, which have a strong anti-inflammatory function and plays major role in Treg-mediated immunosuppression. We found that all of 4 ATLL cell lines (MJ, MT1, MT2, MT4) expressed CD39, but not CD73 just as human effector Tregs. Tumor cells from 12 acute ATLL patients (86%) and 2 chronic ATLL patients (40%) expressed CD39, but the expressions of CD73 were various. Also in asymptomatic carriers, we could detect CD39 and/or CD73 positive in CD7- CADM1+ abnormal fraction of CD4+cells. On the other hand, CD26, normally expressed on human CD4+Th cells other than effector Tregs, was negative in ATLL cell lines and primary ATLL cells except for cells in abnormal fraction of one asymptomatic carrier. CD39 negative cases in chronic/smoldering type tended to show slower disease progression after the blood collection. Next, the role of CD39 and/or CD73 in ATLL cells was assessed in vitro and in vivo. As expected, CD39+ ATLL cells converted significantly more extracellular ATP than CD39- ATLL cells, and mass spectrometry analysis of AMP/adenosine concentration identified the AMPase activity of CD73+ ATLL cells. Furthermore, we established CD39 knockout (KO) cells from ATL cell-line MJ using CRISPR/Cas9 system, and performed in vitro suppression assays for assessment of immunosuppressive function. Although wild type MJ suppressed the growth of normal CD4+ and CD8+ T cells, KO MJ did little. Next, we analyzed the role of CD39 in the progression of tumor cells in vivo. We transplanted mouse T-cell lymphoma cell-line EG7-OVA artificially expressing CD39 or mock into mice subcutaneously. The coinjection of immunoadjuvant poly(I:C) significantly suppressed the tumor growth of mock cells, but the tumor sizes of CD39 expressing cells were almost the same as those of mock cells without poly(I:C) injection (Figure). Conclusion: In this study, we reported that most of ATLL cells in acute type patients express CD39+ CD26- just as Tregs, and that CD39- KO of ATLL cell line cancelled its immunosuppressive effects, and forcibly expressed CD39 on tumor cells rejected the anti-tumor immunity in vivo. From these data, we clarified the pathological mechanism of immunosuppressive function in ATLL cells, and also showed that CD39 expression could be used as a prognostic clue and be a new therapeutic target of ATLL. Disclosures Ezoe: TAIHO Phamaceutical Co., Ltd.: Research Funding. Yokota:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; MSD K.K.: Research Funding. Ichii:Novartis Pharma K.K.: Speakers Bureau; Kowa Pharmaceutical Co.,LTD.: Speakers Bureau; Celgene K.K.: Speakers Bureau. Shibayama:Novartis Pharma K.K.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Takeda Pharmaceutical Co.,LTD.: Honoraria, Research Funding; Fujimoto Pharmaceutical: Honoraria, Research Funding; Jansen Pharmaceutical K.K: Honoraria; Ono Pharmaceutical Co.,LTD: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; Bristol-Meyer Squibb K.K: Honoraria, Research Funding. Oritani:Novartis Pharma: Speakers Bureau. Kanakura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

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Heat Shock Protein 70 Inhibitor, Alone or in Combination with Bortezomib, Prevented Plasmacytoma Development in Immunodeficient Mice Transplanted with Myeloma Cell Lines

Blood ◽

10.1182/blood.v128.22.5658.5658 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5658-5658

Author(s):

Mariana Bleker de Oliveira ◽

Angela Isabel Eugenio ◽

Veruska Lia Fook Alves ◽

Daniela Zanatta ◽

Mihoko Yamamoto ◽

...

Keyword(s):

Cell Line ◽

Tumor Cells ◽

Cell Lines ◽

Proteasome Inhibitor ◽

Conflicts Of Interest ◽

Control Group ◽

Immunodeficient Mice ◽

Late Apoptosis

Abstract Introduction: HSP70 has an integrative role in protein degradation due to the interaction with many pathways, such as ubiquitin proteasome (UPS), unfolded protein response (UPR) and autophagy. In multiple myeloma (MM) HSP70 is overexpressed and helps to prevent proteotoxic stress and cell death caused by overload of unfolded/misfolded proteins produced by tumor cells. Aims: To explore the role of HSP70 inhibition, isolated or in association with proteasome inhibitor, as therapeutic strategy for MM through in vitro and in vivo analyses. Methods: RPMI8226-LUC-PURO and U266-LUC-PURO bioluminescent cell lines were treated with HSP70 inhibitor (VER155008- 50 μM or 80μM) and proteasome inhibitor (bortezomib 100nM) for evaluation of apoptosis induction by flow cytometry using annexin V and propidium iodide. NOD.Cg-rkdcscid Il2rgtm1Wjl/SzJ immunodeficient mice were used for plasmacytoma xenograft model and treated with intravenous VER155008 (40mg/kg) and bortezomib (1mg/kg), immediately after transplant of RPMI8226-LUC-PURO and U266-LUC-PURO bioluminescent cell lines (N=3 for each group, including controls, bortezomib, VER155008, and combination of bortezomib and VER155008). Bioluminescence was measured in IVIS Kinetic (Capiler Life Science) once a day for seven days. Results: Bortezomib used as single treatment was able to induce apoptosis in RPMI8226-LUC-PURO cell line: the best result for in vitro studies RPMI8226-LUC-PURO was 65% of late apoptosis after treatment with bortezomib. On the other hand, U266-LUC-PURO cell line presented higher percentage of apoptosis when treated with bortezomib and VER155008 combination: U266-LUC-PURO cell line presented more than 60% of late apoptosis after VER155008 (80μM) combined with bortezomib, showing that inhibition of HSP70 could overcome U266-LUC-PURO resistance to bortezomib alone. Mice treated with VER155008, alone or in combination with bortezomib, showed complete inhibition of tumor growth (absence of bioluminescence) for both cell lines when compared with control group after one week of treatment (p<0.001, Two-way ANOVA). Therefore, in vivo studies using mice treated with VER155008, alone or in combination with bortezomib, prevented tumor development after one week of treatment, independent of the cell line used in the xenotransplant. Conclusion: Our study shows that HSP70 and proteasome inhibitors combination induced apoptosis in tumor cells in vivo for both MM cell lines. Since HSP70 is overexpressed in MM and connects several signaling pathways that maintain cell survival, such as UPS, UPR and autophagy, it can represent a key role to establish a new approach for the treatment of MM. Financial support: FAPESP 2010/17668-6 and CNPq (155272/2013-6). UNIFESP Ethics Committee (0219/12). Disclosures No relevant conflicts of interest to declare.

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The “Trans-Amplicon” in Myeloma; a Mechanism of Clonal Selection Favoring Retention of Derivative Chromosomes Involved in Translocations.

Blood ◽

10.1182/blood.v106.11.4346.4346 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4346-4346

Author(s):

Azzah Al Masri ◽

Renee Tschumper ◽

Scott Van Wier ◽

Tammy Price-Troska ◽

Diane Jelinek ◽

...

Keyword(s):

Positive Selection ◽

Cell Line ◽

Tumor Cells ◽

Myeloma Cell ◽

Derivative Chromosome ◽

Fusion Signal ◽

Over Time ◽

Selection Of

Abstract Background: Multiple mechanisms exist for the positive selection of genes involved in oncogenesis such as gene amplification and transcriptional deregulation associated with chromosome translocations. Here we describe the case of a myeloma cell line that over time acquired extra copies of a derivative chromosome 4 involved in the t(4;14). These changes occurred over time both in vitro (in the generated JMW myeloma cell lines) as well as in vivo from extramedullary myeloma samples collected from the patient at various time points. In the case of the t(4;14)(p16;q32) 30% can be unbalanced translocations, always with loss of the der(14) and consequent loss of the FGFR3 gene expression, suggesting an indispensable role for MMSET located in the der(4). Results: We performed serial analysis on patient samples obtained at 9, 10 and 12 mos from diagnosis, along with a time course analysis of the cell line. At diagnosis the patient tumor cells displayed a complex clinical karyotype subsequently characterized by hypodiploidy, a t(4;14)(p16;q32), 13 monosomy and 17p13.1-. The remaining chromosome 13 and 17 were involved in an unbalanced reciprocal translocation. Notably, over time the cell line duplicated the total chromosome number becoming near-tetraploid. At the time of diagnosis, FISH analysis was performed on the patient sample revealing the translocation t(4;14)(p16.3:q32) in nearly all cells. The t(4;14) was also present in the stable cell line. It was noted that the patient cells exhibited more than one fusion signal per cell for the t(4;14) by FISH. As the disease progresses both in vitro and in vivo, the number of t(4;14)(p16.3:q32) fusion signals detected per cell increased with time suggesting a positive selection of the derivative chromosomes of the translocation. We further analyzed the t(4;14) in the JMW cells by FISH using MMSET/VH, and FGFR3/CH probe combinations. The full-length (MMSET/FGFR3+VH/CH) probe was used to detect the total number of fusions in the JMW cells. At the time of analysis (cell line passage #23), the majority of the cells (69%) had 6 fusion signals per cell while 23% had 5 fusions and 8% of the cells had 4 fusions. We found that most of the cells (88%) displayed 4 fusion signals detected using the MMSET/VH probes. In parallel studies using the FGFR3/CH probes, 61% of the cells had 2 fusion signals and 39% with 1 fusion signal. It is evident that the tumor cells display positive selection of the derivative chromosome der(4) of the t(4;14)(p16.3;q32), accompanied by an increased dosage of the target gene (MMSET) upregulated by the translocation. Conclusion: We present evidence for the amplification of the translocated chromosome in multiple myeloma, which we have termed “trans-amplicons”. Trans-amplicons may provide a selective growth and survival advantage to the myeloma tumor cells in an analogous manner to amplicons of DNA segments, but with much more powerful transcriptional consequences. Importantly, the evolution of genomic instability exemplified by the “trans-amplicons” in the patient cells was paralleled in vitro in the JMW cells.

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The Heparanase Inhibitor SST0001 Is a Potent Inhibitor of Myeloma Growth In Vivo

Blood ◽

10.1182/blood.v112.11.246.246 ◽

2008 ◽

Vol 112 (11) ◽

pp. 246-246 ◽

Cited By ~ 1

Author(s):

Yang Yang ◽

Joseph P. Ritchie ◽

Telisha Swain ◽

Annamaria Naggi ◽

Giangiacomo Torri ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Heparan Sulfate ◽

Cell Line ◽

Tumor Cells ◽

Subcutaneous Injection ◽

Scid Mice ◽

Rpmi 8226

Abstract Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) chains of proteoglycans. Work by us and others has demonstrated that heparanase promotes the growth and metastasis of many types of tumors, including multiple myeloma (MM). Heparanase expression is rare in normal tissue but becomes evident in many human tumors, making it a viable target for cancer therapy. SST0001, a chemically modified heparin that is 100% N-acetylated and 25% glycol-split, dramatically inhibits heparanase activity. SST0001 lacks anticoagulant activity and thus can be administered at relatively high doses in vivo. We previously reported that delivery of SST0001 by Alzet osmotic pumps to SCID mice potently inhibited growth of subcutaneous tumors formed by CAG human myeloma cells. In the present studies, we further tested the effects of SST0001 against additional MM cell lines, using alternative routes of drug delivery in two different animal models. Ten days after subcutaneous injection of either MM.1S or RPMI 8226 tumor cells, mice were treated for 28 days using Alzet pumps delivering 30 mg/kg/day of SST0001. Results showed that, compared to PBS control, MM.1S and RPMI-8226 tumors in SST0001-treated mice were reduced by 50% and 51%, respectively. In a separate experiment, delivery of SST0001 by distant subcutaneous injection inhibited tumor growth by 77% in comparison to controls. In the SCID-hu model, in which CAG cells were implanted directly into human bones engrafted in SCID mice, SST0001 also significantly inhibited tumor growth as measured by human immunoglobulin kappa light chain in murine sera (1055 ± 295 ng/ml in PBS-treated mice vs 155 ± 295 ng/ml in SST0001- treated mice (P <0.003)). These data demonstrate that SST0001 is a strong inhibitor of MM growth in vivo, even when tumors grow within the bone microenvironment and that the effect of SST0001 is not cell-line specific. We did not observe any adverse side effects in animals, even at doses as high as 120 mg/kg/day. To determine the mechanism of action of SST0001, we examined several pharmacodynamic parameters. Immunohistochemistry demonstrated that SST0001 treatment significantly reduced microvessel density of tumors as compared to controls (99% in CAG and 54% in RPMI-8226 tumors). In addition, SST0001 treatment blocked HGF expression (CAG, RPMI 8226 and MM.1S tumors) and inhibited VEGF expression in CAG tumors but not RPMI 8226 and MM.1S tumors. Moreover, a series of in vitro experiments, using the CAG MM cell line and human umbilical vein endothelial cells (HUVEC), were performed. Unlike its strong antitumor effect in vivo, SST0001 only slightly inhibited CAG cell proliferation, cell cycle and growth factor signaling in vitro, suggesting that the compound does not have a direct cytotoxic effect on tumor cells. Since blood vessels are an important element of the tumor microenvironment and angiogenic endothelium in tumors also expresses high levels of heparan sulfate proteoglycans and heparanase, we assessed the effects of SST0001 on HUVEC cells. In contrast with results on CAG MM cells, SST0001 treatment showed a strong inhibition on HUVEC proliferation (46%, MTT assay), dramatically blocked the phosphorylation of ERK stimulated by HS-binding growth factors (HGF, VEGF, HDGF and EGF), blocked the Akt pathway of HGF signaling in HUVECs and inhibited HUVEC tube formation, stimulated by HGF and VEGF. Based on these results, we conclude that SST0001 strongly inhibits the growth of myeloma tumors in vivo by targeting the tumor microenvironment, including a significant inhibition of tumor angiogenesis. Because of its unique target site in the tumor microenvironment, we predict that the combination of SST0001 with conventional tumor cell-targeting chemotherapeutic drugs will greatly improve patient outcome in MM.

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Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

Nanomaterials ◽

10.3390/nano10040698 ◽

2020 ◽

Vol 10 (4) ◽

pp. 698

Author(s):

Oana-Maria Dragostin ◽

Rodica Tatia ◽

Sangram Keshari Samal ◽

Anca Oancea ◽

Alexandra Simona Zamfir ◽

...

Keyword(s):

Cancer Therapy ◽

Tumor Cells ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Chorioallantoic Membrane ◽

Cancer Therapies ◽

Antiangiogenic Effect ◽

Chitosan Derivatives

Angiogenesis is a physiological process involving the growth of new blood vessels, which provides oxygen and required nutrients for the development of various pathological conditions. In a tumor microenvironment, this process upregulates the growth and proliferation of tumor cells, thus any stage of angiogenesis can be a potential target for cancer therapies. In the present study, chitosan and his derivatives have been used to design novel polymer-based nanoparticles. The therapeutic potential of these newly designed nanoparticles has been evaluated. The antioxidant and MTT assays were performed to know the antioxidant properties and their biocompatibility. The in vivo antiangiogenic properties of the nanoparticles were evaluated by using a chick Chorioallantoic Membrane (CAM) model. The obtained results demonstrate that chitosan derivatives-based nanostructures strongly enhance the therapeutic effect compared to chitosan alone, which also correlates with antitumor activity, demonstrated by the in vitro MTT assay on human epithelial cervical Hep-2 tumor cells. This study opens up new direction for the use of the chitosan derivatives-based nanoparticles for designing of antiangiogenic nanostructured materials, for future cancer therapy.

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The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia

Blood ◽

10.1182/blood-2007-05-092098 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4417-4426 ◽

Cited By ~ 101

Author(s):

Xavier Leleu ◽

Xiaoying Jia ◽

Judith Runnels ◽

Hai T. Ngo ◽

Anne-Sophie Moreau ◽

...

Keyword(s):

Tumor Cells ◽

Akt Pathway ◽

Low Grade ◽

Normal Donor ◽

Down Regulation ◽

Inhibition Of Proliferation ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. We demonstrate up-regulated Akt activity in WM, and that Akt down-regulation by Akt knockdown and the inhibitor perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro, but not in normal donor peripheral blood and hematopoietic progenitors. Importantly, down-regulation of Akt induced cytotoxicity of WM cells in the bone marrow microenvironment (BMM) context. Perifosine induced significant reduction in WM tumor growth in vivo in a subcutaneous xenograft model through inhibition of Akt phosphorylation and downstream targets. We also demonstrated that Akt pathway down-regulation inhibited migration and adhesion in vitro and homing of WM tumor cells to the BMM in vivo. Proteomic analysis identified other signaling pathways modulated by perifosine, such as activation of ERK MAPK pathway, which induces survival of tumor cells. Interestingly, MEK inhibitor significantly enhanced perifosine-induced cytotoxicity in WM cells. Using Akt knockdown experiments and specific Akt and PI3K inhibitors, we demonstrated that ERK activation is through a direct effect, rather than feedback activation, of perifosine upstream ERK pathway. These results provide understanding of biological effects of Akt pathway in WM and provide the framework for clinical evaluation of perifosine in WM patients.

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