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Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.

Identifying novel differentiating agents to promote leukemia-cell differentiation is a pressing need. Here, we demonstrated that vibsanol A, a vibsane-type diterpenoid, inhibited the growth of acute myeloid leukemia (AML) cells via induction of cell differentiation, which was characterized by G1 cell cycle arrest. The differentiation-inducing effects of vibsanol A were dependent upon protein kinase C (PKC) activation, and subsequent activation of the extracellular signal-regulated kinase (ERK) pathway. Furthermore, vibsanol A treatment increased reactive oxygen species (ROS) levels, and the ROS scavenger NAC reversed the vibsanol A-induced cell differentiation, indicating an important role for ROS in the action of vibsanol A. Finally, vibsanol A exhibited a differentiation-enhancing effect when used in combination with all-trans retinoic acid in AML cells. Overall results suggested that vibsanol A induces AML cell differentiation via activation of the PKC/ERK signaling and induction of ROS. Vibsanol A may prove to be an effective differentiating agent against AML.

To identify novel proteins that might help clarify the molecular mechanisms underlying chondromodulin-I (ChM-I) induction of mesenchymal stem cells (MSCs) differentiate into chondrocytes. MSCs are triggered to differentiate into chondrocytes, which are recognized as important factors in cartilage tissue engineering. ChM-I is a glycoprotein that stimulates the growth of chondrocytes and inhibits angiogenesis in vitro. In this study, the proteomic approach was used to evaluate protein changes between undifferentiated MSCs and ChM-I-transfected MSCs. The expression of the protein spots was analyzed using two-dimensional gel electrophoresis. Then, 14 protein spots were identified between MSCs and ChM-I-transfected MSCs. 309 proteins were identified using mass spectrometry (MS). The differentially regulated proteins were categorized and annotated using Protein Analysis Through Evolutionary Relationships (PANTHER) analysis with the aid of the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. These proteins are included in a variety of metabolic pathways and signal transduction pathways, such as focal adhesion, glycolysis, actin cytoskeleton regulation, and ribosome. These results demonstrate novel information about the molecular mechanism by which ChM-I induce MSCs to differentiate into chondrocytes. These results also provide a solid foundation for the development of tissue-engineered cartilage., (Copyright © 2017 Elsevier B.V. All rights reserved.)

All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR., (©2016 American Association for Cancer Research.)

As acute myeloid leukemia (AML) cells are characterized by uncontrolled self-renewal and impaired cellular differentiation, induction of terminal differentiation of leukemia cells by differentiating agents has been proposed as an attractive therapeutic strategy to treat AML. Here, we demonstrated that prostratin, a potent protein kinase C (PKC) activator, inhibited the growth of myeloid leukemia cells by a predominant G1 arrest with variable induction of apoptosis. Conversely, prostratin induced significant differentiation of AML cell lines and primary AML blasts as evidenced by morphology and immunophenotyping. The effects of prostratin were PKC dependent, and activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 by PKC was required for prostratin-induced cell differentiation. Consequently, prostratin reprogrammed transcriptional factor expression, and ectopic expression of c-Myc in HL-60 cells significantly eliminated prostratin-mediated cellular differentiation and cell cycle arrest, indicating an essential role for c-Myc suppression in the differentiation-inducing effects of prostratin. Finally, prostratin was able to potentiate cellular differentiation induced by chemotherapeutic agents such as Ara-C. Together, we proposed that prostratin alone or administered with other anticancer agents may be effective in differentiation therapy of AML., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)