Abstract
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 Ca2+ 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.
Highlights
Leukemia, a group of hematologic malignancies disorder in leukocytes, is characterized by the uncontrolled proliferation and blocked in differentiation of hematopoietic cells [1,2] and subdivided into acute and chronic forms [3]
The potential cytotoxic effects of MJ-29 on WEHI-3 cells were investigated for cell viability by a propidium iodide (PI) exclusion method and using flow cytometric analysis
Our earlier study has reported that MJ-29 exhibited less toxicity in normal cells, including peripheral blood mononuclear cells (PBMC) and human umbilical vein endothelial cells (HUVECs) in comparison to that in the higher sensitive WEHI-3 cells [21]
Summary
A group of hematologic malignancies disorder in leukocytes, is characterized by the uncontrolled proliferation and blocked in differentiation of hematopoietic cells [1,2] and subdivided into acute and chronic forms [3]. They exhibit the blockage of differentiation, enhancement of viability and dysregulation of cell cycle control that is necessary for occurrences of malignant transformation [4]. In the United States, leukemia is the largest number of cases of childhood cancer (approximately 2,000 cases per year) [5]. (Taiwan) indicated that approximately 4.2 per 100,000 individuals die annually from leukemia [6]. New targets for treating leukemia are necessary and the best functions for agents are carried out through promoting differentiation or trigging apoptotic death in leukemia cells [7,8]. The mitochondrial depolarization and activations of caspase family proteases are the central steps when the development of apoptosis [10], and their associated signaling pathways include intrinsic (mitochondria-dependent) and ER stress (unfolded protein response) signals [11,12]
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