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The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy. [ABSTRACT FROM AUTHOR]

Simple Summary: 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is a cyclic oligosaccharide widely used as an excipient in pharmaceutical preparations, in addition to also being used as a cholesterol regulator. HP-β-CyD was used in clinical trials for patients with Niemann-Pick Type C disease to remove accumulated intracellular lipid. HP-β-CyD has anti-leukemia activity by inducing apoptosis and cell-cycle arrest; however, the antitumor activity of HP-β-CyD lacks tumor cell-selectivity. Taking advantage of the fact that folate receptors are highly expressed in many cancer cells, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) to confer tumor cell-selectivity to HP-β-CyD. FA-HP-β-CyD inhibited the proliferation of chronic myeloid leukemia (CML) cells and the mechanism underlying the effect of FA-HP-β-CyD in inducing cell death may involve autophagy. The combination of FA-HP-β-CyD and ABL tyrosine kinase inhibitors (imatinib and ponatinib) had a synergistic inhibitory effect on CML cells. In a mouse model of BCR-ABL-induced leukemia, FA-HP-β-CyD had a stronger inhibitory effect on leukemia progression than HP-β-CyD or imatinib. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia. [ABSTRACT FROM AUTHOR]

The increasing sophistication and complexity of construction technology have also increased workers' physical risk and psychological stress. This study examined the relationships between health risks, work motivation, and productivity as perceived by construction workers. A hypothetical model of worker perceptions, and the psychological factors influencing these perceptions, was developed. A total of 324 construction workers at a Japanese construction company participated in the study and were divided into two groups: younger (45 years of age and below) and older adults (46 years of age and above). Data were collected using a questionnaire. The differences between the age groups were analyzed with regard to their perceptions of health risks, motivation, work skills, and productivity. Both younger and older workers were affected by intrinsic motivations and extrinsic motivations, but the effect of these motivations on work performance differed depending on age. Higher health risks are anticipated to affect the work motivation and productivity perceptions of older workers. The proposed model and findings of this study contribute to understanding worker motivations and have important implications for labor management of construction projects. By addressing construction workers' intrinsic (e.g., interest) and extrinsic (e.g., reward) motivations, it is possible to sustainably improve project productivity.