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Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma.

Yang WC, Lin SF - Biomed Res Int (2015)

Bottom Line: Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments.Although the treatments have improved, the major problem in MM is resistance to therapy.Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Yuan's General Hospital, No. 162, Cheng Kung 1st Road, Kaohsiung 802, Taiwan ; Molecular Medicine Lab, Yuan's General Hospital, No. 162, Cheng Kung 1st Road, Kaohsiung 802, Taiwan ; Faculty of Meiho University, No. 23, Pingguang Road, Neipu, Pingtung 912, Taiwan.

ABSTRACT
Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM.

No MeSH data available.


Related in: MedlinePlus

The mechanism of drug resistance of refractory and relapse multiple myeloma. (a) Microenvironment, (b) clonal evolution of myeloma cells, and (c) cancer stem cell.
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fig1: The mechanism of drug resistance of refractory and relapse multiple myeloma. (a) Microenvironment, (b) clonal evolution of myeloma cells, and (c) cancer stem cell.

Mentions: During conventional chemotherapy such as treatment with vincristine and doxorubicin, accumulation of drugs induces the expression of multidrug resistance (MDR) genes and p-glycoprotein in tumor cells [99–101]. The BM microenvironment can confer drug resistance through two major mechanisms (Figure 1(a)) [102]: (1) tumor cell adhesion, which involves MM cell binding to fibronectin, which in turn induces KIP1 and G1 growth arrest and confers cell-adhesion mediated drug resistance [103, 104] and (2) cytokine-mediated antiapoptotic sequelae, which involve the induction of JAK/STAT and PI3K/AKT signaling by cytokines in the BM microenvironment, which in turn mediates resistance to conventional and novel therapies. IL-6 induces resistance to dexamethasone by activating JAK/STAT signaling and upregulating the antiapoptotic proteins, BCL-XL [105, 106] and myeloid cell leukemia sequence-1 (MCL1) [107, 108]. IL-6 also activates SRC-homology tyrosine phosphatase 2 (SHP2), which blocks dexamethasone-induced activation of RAFTK and apoptosis [109]. Both IL-6 and IGF-1 inhibit drug-induced apoptosis of MM cells through PI3K/AKT signaling and NF-κB activation, which in turn induces the intracellular expression of downstream inhibitor of apoptosis proteins (IAPs), FLICE-inhibitory protein (FLIP), survival, cellular inhibitor of apoptosis-2 (cIAP2), A1/BFL1, and X-linked inhibitor of apoptosis protein (XIAP) [32, 35, 110, 111]. Neither bortezomib nor thalidomide/IMiDs can block JAK/STAT or PI3K/AKT signaling [102].


Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma.

Yang WC, Lin SF - Biomed Res Int (2015)

The mechanism of drug resistance of refractory and relapse multiple myeloma. (a) Microenvironment, (b) clonal evolution of myeloma cells, and (c) cancer stem cell.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663284&req=5

fig1: The mechanism of drug resistance of refractory and relapse multiple myeloma. (a) Microenvironment, (b) clonal evolution of myeloma cells, and (c) cancer stem cell.
Mentions: During conventional chemotherapy such as treatment with vincristine and doxorubicin, accumulation of drugs induces the expression of multidrug resistance (MDR) genes and p-glycoprotein in tumor cells [99–101]. The BM microenvironment can confer drug resistance through two major mechanisms (Figure 1(a)) [102]: (1) tumor cell adhesion, which involves MM cell binding to fibronectin, which in turn induces KIP1 and G1 growth arrest and confers cell-adhesion mediated drug resistance [103, 104] and (2) cytokine-mediated antiapoptotic sequelae, which involve the induction of JAK/STAT and PI3K/AKT signaling by cytokines in the BM microenvironment, which in turn mediates resistance to conventional and novel therapies. IL-6 induces resistance to dexamethasone by activating JAK/STAT signaling and upregulating the antiapoptotic proteins, BCL-XL [105, 106] and myeloid cell leukemia sequence-1 (MCL1) [107, 108]. IL-6 also activates SRC-homology tyrosine phosphatase 2 (SHP2), which blocks dexamethasone-induced activation of RAFTK and apoptosis [109]. Both IL-6 and IGF-1 inhibit drug-induced apoptosis of MM cells through PI3K/AKT signaling and NF-κB activation, which in turn induces the intracellular expression of downstream inhibitor of apoptosis proteins (IAPs), FLICE-inhibitory protein (FLIP), survival, cellular inhibitor of apoptosis-2 (cIAP2), A1/BFL1, and X-linked inhibitor of apoptosis protein (XIAP) [32, 35, 110, 111]. Neither bortezomib nor thalidomide/IMiDs can block JAK/STAT or PI3K/AKT signaling [102].

Bottom Line: Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments.Although the treatments have improved, the major problem in MM is resistance to therapy.Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Yuan's General Hospital, No. 162, Cheng Kung 1st Road, Kaohsiung 802, Taiwan ; Molecular Medicine Lab, Yuan's General Hospital, No. 162, Cheng Kung 1st Road, Kaohsiung 802, Taiwan ; Faculty of Meiho University, No. 23, Pingguang Road, Neipu, Pingtung 912, Taiwan.

ABSTRACT
Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM.

No MeSH data available.


Related in: MedlinePlus