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Resistance to energy metabolism-targeted therapy of AML cells residual in the bone marrow microenvironment

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Cancer Drug Resistance 2023年第1期6卷 138-150页

作者： Yoko Tabe Marina Konopleva Department of Laboratory Medicine Juntendo UniversityTokyo 112-8421Japan Department of Medicine(Oncology)and Molecular Pharmacology Albert Einstein College of MedicineBronxNY 10461USA Department of Leukemia The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic *** meet the biochemical demands of their increased proliferation,AML cells strongly depend on mitochondrial oxidative phosphorylation(OXPHOS).Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation(FAO),which causes uncoupling of mitochondrial OXPHOS and facilitates *** targeting these metabolic vulnerabilities of AML cells,inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic *** experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells,enabling them to acquire resistance against OXPHOS and FAO *** acquired resistance mechanisms compensate for the metabolic targeting by *** chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.

关键词： bone marrow microenvironment acute myeloid leukemia mitochondria oxidative phosphorylation fatty acid oxidation energy metabolism

The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia

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Cancer Drug Resistance 2019年第4期2卷 1164-1177页

作者： Lauren K.Meyer Michelle L.Hermiston Department of Pediatrics University of CaliforniaSan FranciscoSF 94158USA

Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic *** the introduction of intensive multi-agent chemotherapeutic regimens,survival rates for ALL have improved dramatically over the past several decades,though survival rates for adult ALL continue to lag behind those of pediatric *** to chemotherapy remains a significant obstacle in the treatment of ALL,and chemoresistance due to molecular alterations within ALL cells have been *** addition to these cell-intrinsic factors,the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance,and it is now known that stromal cells within the bone marrow microenvironment,through direct cell-cell interactions and through the release of lymphoid-acting soluble factors,contribute to ALL pathogenesis and *** review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.

关键词： Acute lymphoblastic leukemia chemotherapy chemoresistance bone marrow microenvironment

Effect of Ligustrazine on bone marrow microenvironment and Signal Transducti on Path in Irradiation Injured Mice

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Chinese Journal of Integrative Medicine 2002年第4期8卷 295-298页

作者：孙岚刘文励孙汉英任天华李登举徐惠珍路武 Department of Hematology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Objective:To evaluate the effect of ligust razine on bone marrow hematopoietic microenvironment and signal transduction in irradiation injured ***:After being irradiated by 6.0 Gy 60 Co γ -ray, the mice in the ligustrazine group were orally given ligustrazine 4 mg/mouse twice a day to the end of the experiment. For the control group, normal saline was given instead of ligustrazine and the mice in the normal group was untreated. The mice were sacrificed separately on the 3rd, 7th and 14th day after radiation, bone marrow of them was taken and m anaged as follows:(1) Make stromal cell culture to observe the growth state and the expression of focal adhesion kinase (FAK) of the cells; (2) Make the bo ne marrow section to examine the pathological and immunohistochemistry changes, including the expression of fetal liver kinase-1 (Flk-1) and F VIII :RAg. The data were recorded and compared among ***:After radiation, the hematopoietic cells in bo ne marrow decreased and the micro vessels dilated and congested with bleeding; bone mar row became thinner, red colored with cells of irregular shape and few cells adhere to the bottom of culture flask. These changes began to recover at the 7th day and approached to normal within 2 weeks. The recovery was better, earlier and quick er in the ligustrazine group than that in the control group. The expression lev els of Flk-1 decreased ***: Ligustrazine could promote the recovery of hematopoietic function of radiation damaged bone marrow, the mechanisms might be through imp roving the microenvironment and signal transduction path for recovery.

关键词： ligustrazine irradiation injur y fetal liver kinase-1 focal adhesion kinase bone marrow microenvironment

Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca^(2+)-dependent gap junction intercellular communication

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Chinese Medical Journal 2023年第2期136卷 194-206页

作者： Xiaoping Li Yunshuo Xiao Xiaoqi Wang Ruihao Huang Rui Wang Yi Deng Jun Rao Qiangguo Gao Shijie Yang Xi Zhang Department of Hematology 920th Hospital of Joint Logistic Support Force of People’s LiberationKunmingYunnan 650000China Medical Center of Hematology Xinqiao HospitalState Key Laboratory of TraumaBurn and Combined InjuryArmy Medical UniversityChongqing 400037China Department of Cell Biology College of Basic Medicine Army Medical UniversityChongqing 400038China Jinfeng Laboratory Chongqing 401329China

Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca^(2+)-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca ^(2+ )is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions: Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.

关键词： bone marrow microenvironment Connexin 43(Cx43) Gap junction intercellular communication Hypoxia Imatinib resistance

The Effects of Ligustrazine on the Expression of bFGF and bFGFR in bone marrow in Radiation Injured Mice

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第4期23卷 348-351页

作者：吴宁孙汉英刘文励徐慧珍路武 Department of Hematology

To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and Ligustrazine group. After irradiation by 6.0 Gy 60 Co γ ray, each mouse was orally given 0.1 ml Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in radiation injured group was orally given equal amount of saline. On the 3rd, 7th, 14th day after irradiation, bone marrow mono nuclear cells (BMMNC) were counted, and the expression levels of bFGF and bFGFR in bone marrow were evaluated by immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th, 14th day after irradiation, expression of bFGF in bone marrow were significantly lower than in normal group ( P bone marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment, which is one of the mechanisms by which Ligustrazine rebuild the bone marrow hematopoiesis after acute radioactive injury.

关键词： Ligustrazine bFGF bFGFR bone marrow microenvironment irradiation

Communication between bone marrow mesenchymal stem cells and multiple myeloma cells:Impact on disease progression

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World Journal of Stem Cells 2023年第5期15卷 421-437页

作者： Daniel García-Sánchez Alberto González-González Ana Alfonso-Fernández Mónica Del Dujo-Gutiérrez Flor M Pérez-Campo Department of Molecular Biology_IDIVAL Faculty of MedicineUniversity of CantabriaSantander 39011CantabriaSpain Servicio de Traumatología y Cirugía Ortopédica Hospital Universitario Marqués de ValdecillaInstituto de Investigación Sanitaria Valdecilla(IDIVAL)Facultad de MedicinaUniversidad de CantabriaSantander 39008CantabriaSpain

Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this *** data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological *** relation of MM cells with the resident BM-MSCs is a two-way *** modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence *** turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease *** interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other ***,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling ***,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

关键词： Multiple myeloma Mesenchymal stem cells bone marrow microenvironment Soluble factors Extra-cellular vesicles Cells adhesion molecules Tunnellingnanotubes

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Cancer Drug Resistance 2023年第4期6卷 838-857页

作者： Gil Kozalak Ali Kosar Faculty of Engineering and Natural Science Sabanci UniversityIstanbul 34956Turkey Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics(EFSUN) Sabanci UniversityIstanbul 34956Turkey Turkish Academy of Sciences(TUBA) CankayaAnkara 06700Turkey

Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become *** drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treatment of ***,a type 2 cell death mechanism,plays a crucial role in determining the fate of B cells,either promoting their survival or inducing cell ***,autophagy can either facilitate the progression or hinder the treatment of MM *** this review,autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response(UPR),bone marrow microenvironment(BMME),drug resistance,hypoxia,DNA repair and transcriptional regulation,and *** genes that are effective in each mechanism and research efforts on this subject were discussed in *** pathways targeted by new drugs to benefit from autophagy in MM disease were *** efficacy of drugs that regulate autophagy in MM was examined,and clinical trials on this subject were ***,among the autophagy mechanisms that are effective in MM,the most suitable ones to be used in the treatment were *** importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was ***,this review aims to provide a comprehensive overview of MM disease,encompassing autophagy mechanisms,drugs,clinical studies,and further studies.

关键词： Autophagy multiple myeloma unfolded protein response bone marrow microenvironment drug resistance hypoxia DNArepairandtranscriptional regulation apoptosis

Therapeutics to harness the immune microenvironment in multiple myeloma

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Cancer Drug Resistance 2022年第3期5卷 647-661页

作者： James J.Ignatz-Hoover James J.Driscoll University Hospitals Seidman Cancer CenterClevelandOH 44106USA Department of Biochemistry Case Western Reserve UniversityClevelandOH 44106USA Hematopoietic and Immune Cancer Biology Program Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandOH 44106USA

Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)*** therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune *** inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma ***,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient *** current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease *** logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to *** complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging *** cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug ***,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug *** effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

关键词： Multiple myeloma drug resistance proteasome inhibitors immunomodulators immunotherapeutics adaptive resistance bone marrow microenvironment

Clinical Observation on Effect of Shuanghuang Shengbai Granule (双黄升白冲剂) on Chemotherapy Induced Myelosuppression in Tumor Patients and on Ultrastructure of bone marrow in Mice

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Chinese Journal of Integrative Medicine 2001年第4期7卷 277-282页

作者：徐振晔朱晏伟周卫东张晖鞠艳芳赵丽红邓海滨吴继沈德义张蕙心 Longhua Hospital affiliated to Shanghai TCM University Shanghai200032 Hebei Provincial Hospital of Tumor Department of Electron Microscopy Shanghai Second Medical University

To observe the leucocyte increasing effect of Shuanghuang Shengbai Granule (SHSBG) in tumor patients treated by chemotherapy and the bone marrow microenvironment protecting effect in ***: Patients of non-small-cell pulmonary, mammary, gastric or intestinal cancer, who were ready for receiving re-treatment of chemotherapy, were enrolled and divided into 4 groups randomly. The 28 cases in SHSBG group A received chemotherapy combined with SHSBG; the 27 in the SHSBG group B received chemotherapy alone at first, and SHSBG was added when their peripheral white blood cell (WBC) count lowered to ＜4×109/L; the 33 in control group A and 24 in control group B were treated by the method similar to that applied to SHSBG group A and B respectively but with Rubidate instead of SHSBG. Experimental study of electron microscopic observation on bone marrow ultrastructure in mice was also ***: The total leukocyte increasing effective rate occurred in SHSBG group A and B was 75.00% and 88.89%, while in control group A and B, 54.55% and 58.33% respectively, and the difference between the SHSBG groups and the control groups was significant (Pbone marrow hematopoietic microenvironment protecting and improving effect in ***: SHSBG has obvious protecting and treating effect on chemotherapy induced bone marrow suppression in tumor patients.

关键词： Shuanghuang Shengbai Granule chemotherapy-caused bone marrow suppression leukocyte increasing bone marrow microenvironment