Novel Quinazolinone MJ-29 Triggers Endoplasmic Reticulum Stress and Intrinsic Apoptosis in Murine Leukemia WEHI-3 Cells and Inhibits Leukemic Mice

• Published in: PLoS ONE Vol. 7; no. 5; p. e36831
• Main Authors: Lu, Chi-Cheng, Yang, Jai-Sing, Chiang, Jo-Hua, Hour, Mann-Jen, Lin, Kuei-Li, Lin, Jen-Jyh, Huang, Wen-Wen, Tsuzuki, Minoru, Lee, Tsung-Han, Chung, Jing-Gung
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 25.05.2012; Public Library of Science
• Subjects: Animal tissues; Animals; Annexin V; Antigens, CD; Antigens, CD - metabolism; Antineoplastic Agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; B cells; Biology; Body Weight; Body Weight - drug effects; Calcium; Calcium (intracellular); Calcium - metabolism; Calpain; Cancer therapies; Cell cycle; Cell Cycle Checkpoints; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival; Cell Survival - drug effects; Chemotherapy; Cytometry; Cytotoxicity; Deoxyribonucleic acid; DNA; Drug resistance; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoplasmic Reticulum Stress - drug effects; Flow cytometry; Immune response; Immunotherapy; Infiltration; Intracellular signalling; Leukemia; Leukemia - drug therapy; Leukemia - metabolism; Leukemia - mortality; Leukocytes, Mononuclear; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Life sciences; Liver; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes B; Macrophages; Macrophages - drug effects; Macrophages - immunology; Male; Medicine; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria - drug effects; Monocytes; Myelomonocytic leukemia; Organ Size; Organ Size - drug effects; Permeability; Phagocytosis; Phagocytosis - drug effects; Pharmaceuticals; Proteins; Pulp; Q; Quinazolinone; Quinazolinones; Quinazolinones - pharmacology; R; Reactive Oxygen Species; Red pulp; Research Article; Science; Signal Transduction; Signal Transduction - drug effects; Spleen; Stress; Stresses; Survival; Unfolded Protein Response; Unfolded Protein Response - drug effects; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036831

The present study was to explore the biological responses of the newly compound, MJ-29 in murine myelomonocytic leukemia WEHI-3 cells in vitro and in vivo fates. We focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. Our results indicated that a concentration-dependent decrease of cell viability was shown in MJ-29-treated cells. DNA content was examined utilizing flow cytometry, whereas apoptotic populations were determined using annexin V/PI, DAPI staining and TUNEL assay. Increasing vital factors of mitochondrial dysfunction by MJ-29 were further investigated. Thus, MJ-29-provaked apoptosis of WEHI-3 cells is mediated through the intrinsic pathway. Importantly, intracellular Ca(2+) release and ER stress-associated signaling also contributed to MJ-29-triggered cell apoptosis. We found that MJ-29 stimulated the protein levels of calpain 1, CHOP and p-eIF2α pathways in WEHI-3 cells. In in vivo experiments, intraperitoneal administration of MJ-29 significantly improved the total survival rate, enhanced body weight and attenuated enlarged spleen and liver tissues in leukemic mice. The infiltration of immature myeloblastic cells into splenic red pulp was reduced in MJ-29-treated leukemic mice. Moreover, MJ-29 increased the differentiations of T and B cells but decreased that of macrophages and monocytes. Additionally, MJ-29-stimulated immune responses might be involved in anti-leukemic activity in vivo. Based on these observations, MJ-29 suppresses WEHI-3 cells in vitro and in vivo, and it is proposed that this potent and selective agent could be a new chemotherapeutic candidate for anti-leukemia in the future.