ku-55933 and Multiple-Myeloma

Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia-mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors. Specifically, IL-6-containing conditioned media (CM) derived from Dox-pretreated stromal cells displayed significant protective effect on Dox-induced apoptosis of MM cells. Also, treatment of BMSCs with ATM kinase inhibitor markedly reduced IL-6 secretion and concurrently, partially reversed CM-mediated chemoresistance in myeloma cells. These data indicate that DNA-damaging drug triggers an ATM-dependent DDR in BMSCs, leading to increased cytokine secretion and resistance of myeloma cells to chemotherapy-induced apoptosis.

Topics: Antibiotics, Antineoplastic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line; Cell Line, Tumor; Cells, Cultured; DNA Damage; Doxorubicin; Drug Resistance, Neoplasm; Humans; Interleukin-6; Mesenchymal Stem Cells; Morpholines; Multiple Myeloma; Pyrones

This study was aimed to explore the effect of a novel histone deacetylase inhibitor Chidamide on apoptosis of human multiple myeloma(MM) cells and its relevance to DNA damage response(DDR).. The cell proliferation was detected by MTT method, apoptosis and cell cycle distribution were analyzed by flow cytometry, the expression levels of targeted proteins were detected by Western blot, the DNA damage response was blocked by ATM kinase inhibitor KU-55933.. Chidamide inhibited RPMI 8226 cell proliferation in dose- and time-dependent manner and its IC50 values of 24,48,72 h were 9.6, 6 and 2.8 µmol/L respectively. Chidamide induced cell cycle arrest of RPMI 8226 cells in G0/G1 phase by upregulating the expression of P21. Chidamide triggered caspase-3 dependent apoptosis and upregulated expression of DDR-related proteins including γH2AX, pATM in RPMI 8226 cells. Pretreatment with ATM kinase inhibitor KU-55933 down-regulated expression of DDR related proteins induced by chidamide, thereby inhibiting DNA damage response and finally resulting in suppression of apoptotic cell death.. Proliferative inhibtion, cell cycle arrest and apoptosis of multiple myeloma cells induced by chidamide involve DDR.

Topics: Aminopyridines; Apoptosis; Benzamides; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA Damage; Down-Regulation; Flow Cytometry; Histone Deacetylase Inhibitors; Humans; Morpholines; Multiple Myeloma; Pyrones

There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA damage response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) pharmacologic inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs.

Topics: Antibiotics, Antineoplastic; Antigens, Differentiation, T-Lymphocyte; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Ataxia Telangiectasia Mutated Proteins; Caffeine; Cell Cycle Proteins; Cell Degranulation; Cell Line, Tumor; Cellular Senescence; DNA-Binding Proteins; Doxorubicin; GPI-Linked Proteins; Humans; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Melphalan; Morpholines; Multiple Myeloma; Phosphodiesterase Inhibitors; Protein Serine-Threonine Kinases; Pyrones; Tumor Suppressor Proteins; Up-Regulation