Menin‑MLL inhibitors induce ferroptosis and enhance the anti‑proliferative activity of auranofin in several types of cancer cells.

Menin‑mixed‑lineage leukemia (MLL) inhibitors have potential for use as therapeutic agents for MLL‑rearranged leukemia. They are also effective against solid cancers, such as breast cancer. The present study demonstrated that menin‑MLL inhibitors, such as MI‑463, unexpectedly induced the ferroptotic cell death of several cancer cell lines.

Effect of Cytokines and Hyperthermia on Phagocytosis and Phosphatidylserine Externalization: Implication for the Pathophysiology of Hemophagocytic Syndrome.

Objective: An aberrant production of inflammatory cytokines, with resultant febrile response, is a cardinal finding of hemophagocytic syndrome. A role of inflammatory cytokines on phagocytosis and clearance of apoptotic cells or particles has been shown, but effects of cytokines or hyperthermia on phagocytosis of viable blood cells were not fully understood. We examined effects of cytokines and hyperthermia on phagocytosis, and externalization of phosphatidylserine on the surface of phagocytosed blood cells, to clarify the pathophysiology of hemophagocytic syndrome.

TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells.

Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy.

NM23 downregulation and lysophosphatidic acid receptor EDG2/lpa1 upregulation during myeloid differentiation of human leukemia cells.

The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis.

Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis.

Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required.

Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells.

The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines.

Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells.

Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells.

Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells.

Arsenic trioxide (ATO) is an approved treatment for acute promyelocytic leukemia (APL). It has also shown potential for treatment of multiple myeloma and various solid tumors including breast cancer. The requirement of high, toxic concentrations for the induction of apoptosis in non-APL and solid tumor cells is a major limitation for its use in other hematological malignancies and solid tumors.

Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells.

Cotylenin A, a plant growth regulator, and rapa-mycin, an inhibitor of the mammalian target of rapamycin, are potent inducers of differentiation in myeloid leukemia cells and also synergistically inhibit the proliferation of several human breast cancer cell lines including MCF-7 in vitro and in vivo. However, the mechanisms of the combined effects of cotylenin A and rapamycin are still unknown. Activated Akt induced by rapamycin has been suggested to attenuate the growth-inhibitory effects of rapamycin, serving as a negative feedback mechanism.

Extracellular NM23 Protein as a Therapeutic Target for Hematologic Malignancies.

An elevated serum level of NM23-H1 protein is a poor prognostic factor in patients with various hematologic malignancies. The extracellular NM23-H1 protein promotes the in vitro growth and survival of acute myelogenous leukemia (AML) cells and inversely inhibits the in vitro survival of normal peripheral blood monocytes in primary culture at concentrations equivalent to the levels found in the serum of AML patients. The growth and survival promoting activity to AML cells is associated with cytokine production and activation of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways.

Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells.

All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK.

Extracellular NM23 protein promotes the growth and survival of primary cultured human acute myelogenous leukemia cells.

An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML), and predicts a poor treatment outcome in AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro growth and survival of primary cultured AML cells at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein promoted the in vitro growth and survival of AML cells and this activity was associated with the cytokine production and activation of the MAPK and signal transducers and activators of transcription signaling pathways.

Extracellular NM23-H1 protein inhibits the survival of primary cultured normal human peripheral blood mononuclear cells and activates the cytokine production.

An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML) and predicts a poor treatment outcome for AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro survival of primary cultured normal peripheral blood mononuclear cells (PBMNC) at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein inhibited the in vitro survival of PBMNC and promoted the production of various cytokines, such as GM-CSF and IL-1beta, which in fact promoted the growth of primary cultured AML cells.

Cotylenin A, a new differentiation inducer, and rapamycin cooperatively inhibit growth of cancer cells through induction of cyclin G2.

Cotylenin A, a plant growth regulator, and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), are potent inducers of differentiation of myeloid leukemia cells. Recently, we found that cotylenin A and rapamycin effectively inhibited the proliferation of several human breast cancer cell lines including MCF-7. Herein, we demonstrate that cotylenin A and rapamycin rapidly and markedly induced the cyclin G2 gene expression in several cancer cells including MCF-7 cells.

Cotylenin A-induced differentiation is independent of the transforming growth factor-beta signaling system in human myeloid leukemia HL-60 cells.

Cotylenin A, which has been isolated as a plant growth regulator, potently induces the differentiation of human myeloid leukemia cells. Treatment of HL-60 cells with a combination of transforming growth factor (TGF)-beta and 1alpha, 25-dihydroxyvitamin D(3) (VD3) resulted in increased differentiation compared to separate treatments, but TGF-beta did not affect the cotylenin A-induced differentiation of HL-60 cells. It is possible that the signal transduction pathway used by cotylenin A for inducing the differentiation of leukemia cells is the same as that used by TGF-beta.

Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts.

Introduction: Rapamycin, an inhibitor of the serine/threonine kinase target of rapamycin, induces G1 arrest and/or apoptosis. Although rapamycin and its analogues are attractive candidates for cancer therapy, their sensitivities with respect to growth inhibition differ markedly among various cancer cells. Using human breast carcinoma cell line MCF-7 as an experimental model system, we examined the growth-inhibitory effects of combinations of various agents and rapamycin to find the agent that most potently enhances the growth-inhibitory effect of rapamycin.

Clinical significance of serum NM23-H1 protein in neuroblastoma.

We have previously reported that NM23 genes are overexpressed in various hematological malignancies and that serum NM23-H1 protein levels are useful for predicting patient outcomes. In this study we assessed the clinical implications of serum NM23-H1 protein on neuroblastoma. We examined serum NM23-H1 protein levels in 217 patients with neuroblastoma, including 131 found by mass-screening and 86 found clinically by an enzyme-linked immunosorbent assay, and determined the association between levels of this protein, and known prognostic factors or the clinical outcome.

Immediate up-regulation of the calcium-binding protein S100P and its involvement in the cytokinin-induced differentiation of human myeloid leukemia cells.

Cytokinins are important purine derivatives that act as redifferentiation-inducing hormones to control many processes in plants. Cytokinins such as isopentenyladenine (IPA) and kinetin are very effective at inducing the granulocytic differentiation of human myeloid leukemia HL-60 cells. We examined the gene expression profiles associated with exposure to IPA using cDNA microarrays and compared the results with those obtained with other inducers of differentiation, such as all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 (VD3) and cotylenin A (CN-A).

Antitumor effect of cotylenin A plus interferon-alpha: possible therapeutic agents against ovary carcinoma.

Objective: Recently, we found that cotylenin A and IFNalpha synergistically inhibited growth both in vitro and in vivo, and induced apoptosis in human cancer cells. For the clinical application of this combined treatment, suitable cancer targets should be selected.

Methods: We examined the combined effects of these compounds on various types of cancer cells by a human cancer cell line panel assay, and on cancer cells that had been freshly isolated from patients in three-dimensional cultures embedded in collagen gel.

Induction of CCAAT/enhancer binding protein-delta by cytokinins, but not by retinoic acid, during granulocytic differentiation of human myeloid leukaemia cells.

Cytokinins, purine derivatives that act as hormones to control many processes in plants, are very effective at inducing the granulocytic differentiation of human myeloid leukaemia cells. Isopentenyladenine (IPA), a potent cytokinin, significantly induced the expression of CCAAT/enhancer-binding protein (C/EBP)delta, but not C/EBP alpha protein, whereas all-trans retinoic acid, a well-known inducer of granulocytic differentiation, induced C/EBP alpha but not C/EBP delta protein. Antisense oligonucleotide for C/EBP delta, but not C/EBP alpha or C/EBP beta, effectively suppressed IPA-induced differentiation, suggesting that the expression of C/EBP delta protein is necessary for cytokinin-induced differentiation.

MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia.

We previously found that expression of the Mm-1 cell-derived transplantability-associated gene 1b (MmTRA1b)/phospholipid scramblase 1 gene was markedly induced during the granulocytic differentiation of human myeloid leukemia cells. To evaluate the role of MmTRA1b expression in human myeloid leukemia, we investigated the relative levels of MmTRA1b transcripts in 81 patients with acute myelogenous leukemia (AML) by the reverse transcriptase polymerase chain reaction. The expression of MmTRA1b in AML-M1, -M5a and -M5b was significantly lower than that in normal bone marrow cells.

Induction of apoptosis by combined treatment with differentiation-inducing agents and interferon-alpha in human lung cancer cells.

Background: Differentiation-inducing agents for myeloid leukemic cells, such as dimethyl sulfoxide (DMSO), Na-butyrate and hexamethylene-bis-acetamide (HMBA), barely induce irreversible differentiation or growth inhibition in solid tumors when used alone. However, we previously reported that combined treatment with differentiation-inducing agents and interferon (IFN)-alpha effectively suppressed the growth of human lung cancer cell lines in vitro and in vivo. We show here that combined treatment-induced cell death is caused by apoptosis.

Physiological and pathological relevance of extracellular NM23/NDP kinases.

The NM23 gene is overexpressed in many hematological malignancies and other neoplasms. Some tumor cell lines that overexpress NM23 secrete this protein into extracellular environment. In this study, we found that the serum concentration of NM23-H1 protein was significantly higher in patients with various hematological malignancies.

Role of MmTRA1b/phospholipid scramblase1 gene expression in the induction of differentiation of human myeloid leukemia cells into granulocytes.

Objective: We previously cloned a human normal counterpart (MmTRA1b/phospholipid scramblase 1) of the mouse leukemogenesis-associated gene MmTRA1a. MmTRA1b gene expression was increased during differentiation of human monoblastic leukemia U937 cells using some differentiation inducers but not 1alpha,25-dihydroxyvitamin D(3) (a typical monocytic differentiation inducer). To further elucidate the role of human MmTRA1b gene expression in the differentiation of myelogenous leukemia cells, we measured MmTRA1b gene expression in several myeloid leukemia cell lines and primary leukemia cells.

Expression of cell surface NM23 proteins of human leukemia cell lines of various cellular lineage and differentiation stages.

Cell surface expression of NM23 protein is only observed on tumor cell lines, but not on normal cells. To examine what types of tumor cell line express the cell surface NM23 protein, we measured the cell surface NM23-H1 and NM23-H2 proteins of leukemia line cells on various cellular lineage and differentiation stages. The NM23-H1 was expressed on myeloid leukemia lines but not lymphoid lines, while NM23-H2 was only expressed on erythroleukemia lines.