curcumin and Leukemia--Myeloid--Acute

Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs. Multidrug resistance (MDR) is a complex process determined by multiple mechanisms, and it is often caused by the overexpression of efflux pumps, the most important of which is P-glycoprotein (P-gp). This mini-review aims to examine the advantages of using natural substances as P-gp inhibitors, focusing on four molecules: phytol, curcumin, lupeol, and heptacosane, and their mechanism of action in AML.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute

This study aimed to evaluate the effects of curcumin by co-administration of arsenic trioxide (As. Using Pubchem database, Traditional Chinese Medicine Information Database (TCMID) database, and Swiss target prediction database to predict compound-related targets, AML-associated targets were determined using GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. We identify overlapping common targets by comparing Compounds-related and AML-associated targets and using these targets to perform GO and KEGG functional enrichment analyses. Subsequently, these targets were input into the STRING database, and we used Cytoscape to construct protein-protein interaction (PPI) network. Finally, we used KG1-a cells and the AML mouse model to measure the anti-leukemia effects of curcumin and As. Compounds and targets screening hinted that 85 intersection targets were predicted in the curcumin treatment of AML, 75 targets in the As

Topics: Animals; Arsenic Trioxide; Curcumin; Drugs, Chinese Herbal; Leukemia, Myeloid, Acute; Mice; Network Pharmacology; Tumor Suppressor Protein p53

To address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML).. A xenograft AML mouse model was established by injecting HL-60 cells into tail vein of mice to assess the function of Curcumin. Mononuclear cells (MNCs) isolated from AML mice and AML cell lines were used to examine the effect of Curcumin. Metagenomics and metabolomics were used to evaluate the alteration of intestinal microbiota and the change of metabolites in MNCs.. Curcumin treatment sensitized response to Ara-C in MNCs of AML mice, but had no direct effect on AML cell lines. Metagenomics revealed an alteration of intestinal microbiota with Curcumin treatment, which contributes to sensitized response to Ara-C. Curcumin treatment led to enhanced intestinal intact to sensitize response to Ara-C in AML mice, through reducing mucus degrading bacteria. Metabolomics demonstrated that Curcumin treatment led to decreased cholesterol in MNCs of AML mice. Further study proved that Curcumin treatment resulted in inhibition of SQLE, a key enzyme of cholesterol biosynthesis, to increase sensitivity to Ara-C.. Curcumin sensitizes response to Ara-C through regulating microbiota, highlighting the importance of intestinal intact strengthening in chemoresistant therapy. Moreover, aiming at cholesterol synthesis is promising in AML treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cholesterol; Curcumin; Cytarabine; Drug Resistance, Neoplasm; Drug Synergism; Gastrointestinal Microbiome; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Metabolomics; Metagenomics; Mice; Xenograft Model Antitumor Assays

Curcumin, the primary bioactive component isolated from turmeric, has been found to possess a variety of biological functions, including anti-leukemia activity. However, the effect of curcumin in different leukemia cells vary. In this study, we demonstrated that curcumin induced the expression of AIM2, IFI16, and NLRC4 inflammasomes in leukemia cells U937 by increasing the expression levels of ISG3 transcription factor complex, which activated caspase 1, promoted cleavage of GSDMD, and induced pyroptosis. We also found that pyroptosis executor GSDMD was not expressed in two curcumin-insensitive cells HL60 and K562 cells. In addition, exogenous overexpression of GSDMD by lentiviral transduction in K562 cells increased the anti-cancer activity of curcumin, and inhibiting the expression of GSDMD by shRNA enhanced U937 cells to resist curcumin. The results showed that inducing pyroptosis is a novel mechanism underlying the anti-leukemia effects of curcumin.

Topics: Calcium-Binding Proteins; CARD Signaling Adaptor Proteins; Curcumin; DNA-Binding Proteins; Humans; Inflammasomes; Leukemia, Myeloid, Acute; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear Proteins; Phosphoproteins; Pyroptosis; U937 Cells

The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC

Topics: Cell Line, Tumor; Curcumin; Ellagic Acid; Glycolysis; Humans; Leukemia, Myeloid, Acute; Pyruvate Kinase; Resveratrol; Silybin

Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), particularly for those at high-risk for relapse. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In the present study, expression signatures of different miRs related both to presence of myeloid/lymphoid or mixed-lineage leukaemia 1 and Fms like tyrosine kinase 3 internal tandem duplications rearrangements and to the clinical outcome of paediatric patients with AML were identified. Notably, miR-221-3p and miR-222-3p resulted as a possible relapse-risk related miR. Thus, miR-221-3p and miR-222-3p expression modulation was investigated by using a Bromodomain‑containing protein 4 (BRD4) inhibitor (JQ1) and a natural compound that acts as histone acetyl transferase inhibitor (curcumin), alone or in association, in order to decrease acetylation of histone tails and potentiate the effect of BRD4 inhibition. JQ1 modulates miR-221-3p and miR-222-3p expression in AML with a synergic effect when associated with curcumin. Moreover, changes were observed in the expression of

Topics: Apoptosis; Cell Cycle Proteins; Child; Curcumin; Histones; Humans; Leukemia, Myeloid, Acute; MicroRNAs; Neoplasm Recurrence, Local; Nuclear Proteins; Transcription Factors

Acute myeloid leukemia (AML) is an aggressive blood cancer with limited chemotherapy options and negative patient outcomes. Investigations with bioactive compounds from dietary sources against cancer have increased in the recent years, which highlight the need for novel therapeutic approaches and new anti-leukemic agents possessing higher efficacy and selectivity for AML cells and fewer negative side effects. Bioactive compounds demonstrated the ability to induce cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration and tumor progression, etc. Bioactive compounds isolated from dietary sources such as mango ginger show promise for AML treatment. Curcuma amada roots have been used in traditional medicine and showed antioxidant, antimicrobial and anticancer properties. Bioactive molecules isolated from C. amada showed effects on the mitochondrial metabolism and reduced the viability of multiple leukemic cell lines.

Topics: Apoptosis; Curcuma; Humans; Leukemia, Myeloid, Acute

Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

Topics: Animals; Azepines; Benzylidene Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Embryo, Nonmammalian; Endoplasmic Reticulum Stress; Glutathione; Heme Oxygenase-1; Humans; Leukemia, Myeloid, Acute; Molecular Weight; Polyubiquitin; Proteasome Endopeptidase Complex; Time Factors; Ubiquitin; Ubiquitination; Zebrafish

This study aims to enhance efficacy and reduce toxicity of the combination treatment of a drug and curcumin (Cur) on leukemic stem cell and leukemic cell lines, including KG-1a and KG-1 (FLT3

Topics: Antigens, Neoplasm; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcuma; Curcumin; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Neoplastic; Humans; Idarubicin; Leukemia, Myeloid, Acute; Rhizome

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of

Topics: Animals; Curcumin; Disease-Free Survival; DNA-Binding Proteins; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Heme; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Myelodysplastic Syndromes; Promoter Regions, Genetic; Transcription Factors

Curcumin, a phytochemical from rhizomes of the plant

Topics: Animals; Apoptosis; Catechin; Cell Cycle Checkpoints; Cell Line, Tumor; Curcumin; Genistein; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; U937 Cells

Cytarabine is a key chemotherapy drug for treating leukemia; however, chemotherapy‑induced multidrug resistance is a major cause of therapy failure or tumor recurrence. Current medical treatment strategies still cannot address the issue of multidrug resistance phenotypes in the treatment of leukemia. Curcumin counteracts tumor development by inducing apoptosis in cytarabine‑resistant acute myeloid leukemia cells. Branched‑chain amino acid transaminase 1 (BCAT1), an aminotransferase enzyme, acts on branched‑chain amino acids. Moreover, the aberrant expression of BCAT1 has been observed in numerous cancer cells, and BCAT1 serves a critical role in the progression of myeloid leukemia. BCAT1 can interfere with cancer cell proliferation by regulating mTOR‑mediated mitochondrial biogenesis and function. The present study aimed to investigate whether curcumin induces apoptosis by regulating BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells. Four leukemia cell lines and three primary myeloid leukemia cells were treated with curcumin, and the expression and activity of BCAT1 and mTOR were investigated by reverse transcription‑quantitative PCR, western blotting and α‑KG quantification assay. The results demonstrated that curcumin inhibited BCAT1 expression in Kasumi‑1, KG‑1, HL60, cytarabine‑resistant HL60, and cytarabine‑resistant primary myeloid leukemia cells. Notably, tetrahydrocurcumin, a major metabolite of curcumin, and cytarabine had no inhibitory effect on BCAT1 expression. Furthermore, BCAT1 and mTOR signaling may modulate each other in cytarabine‑resistant HL60 cells. The present results indicated that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways. Thus, understanding the mechanism underlying curcumin‑induced apoptosis in cytarabine‑resistant cells can support the development of novel drugs for leukemia.

Topics: Adolescent; Apoptosis; Cell Line, Tumor; Child; Curcumin; Cytarabine; Drug Resistance, Neoplasm; Female; Humans; Indoles; Ketoglutaric Acids; Leukemia, Myeloid, Acute; Male; Purines; Signal Transduction; TOR Serine-Threonine Kinases; Transaminases

Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer suppressive effects and increases sensitivity to chemotherapy in several diseases. This study aimed to investigate the mechanism by which curcumin affects the resistance of AML to Adriamycin by regulating HOX transcript antisense RNA (HOTAIR) expression. Cell viability, colony-formation, flow cytometry, and Transwell assays were used to assess cell proliferation, apoptosis, and migration. A dual-luciferase reporter assay was used to verify the interaction between microRNA (miR)-20a-5p and HOTAIR or Wilms' tumor 1 (WT1). RT-qPCR and Western blotting assays were performed to detect gene and protein expression. The results showed that curcumin suppressed the resistance to Adriamycin, inhibited the expression of HOTAIR and WT1, and promoted the expression of miR-20a-5p in human acute leukemia cells (HL-60) or Adriamycin-resistant HL-60 cells (HL-60/ADR). Furthermore, curcumin suppressed proliferation and promoted apoptosis of HL-60/ADR cells. Overexpression of HOTAIR reversed the regulatory effect of curcumin on apoptosis and migration and restored the effect of curcumin on inducing the expression of cleaved caspase3, Bax, and P27. In addition, HOTAIR upregulated WT1 expression by targeting miR-20a-5p, and inhibition of miR-20a-5p reversed the regulation of Adriamycin resistance by curcumin in AML cells. Finally, curcumin inhibited Adriamycin resistance by suppressing the HOTAIR/miR-20a-5p/WT1 pathway in vivo. In short, curcumin suppressed the proliferation and migration, blocked the cell cycle progression of AML cells, and sensitized AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.

Topics: Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; MicroRNAs; RNA, Long Noncoding; Signal Transduction; WT1 Proteins

Acute myeloid leukemia (AML) is a type of blood disorder that exhibits uncontrolled growth and reduced ability to undergo apoptosis. Signal transducer and activator of transcription 3 (STAT3) is a family member of transcription factors which promotes carcinogenesis in most human cancers. This effect on AML is accomplished through deregulation of several critical genes, such as B cell lymphoma-extra-large (BCL-XL) which is anti-apoptotic protein. The aim of this study was to evaluate the effect of curcumin (CUR) and thalidomide (THAL) on apoptosis induction and also the alteration of the mRNA expression level of STAT3 and BCL-XL mRNA on AML cell line compounds.. The growth inhibitory effects of CUR and THAL and their combination were measured by MTT assay in U937 and KG-1 cell lines. The rates of apoptosis induction and cell cycle analysis were measured by concurrent staining with Annexin V and PI. The mRNA expression level of STAT3 and BCL-XL was evaluated by Real-Time PCR.. CUR inhibited proliferation and induced apoptosis in both KG-1 and U937 cells and this effect increased by combination with THAL. The expression level of STAT3 and BCL-XL was significantly down-regulated in KG-1 cells after treatment by CUR and THAL and their combination.. Overall, our findings suggested that down-regulation of STAT3 and BCL-XL mRNA expression in response to CUR and THAL treatment lead to inhibition of cell growth and induction of apoptosis.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Leukemia, Myeloid, Acute; STAT3 Transcription Factor; Structure-Activity Relationship; Thalidomide; Tumor Cells, Cultured

Most anticancer agents induce cancer cell death; however, multidrug-resistant cancers often lead to treatment failure. The effective use of curcumin as an anticancer agent has been demonstrated in clinical trials. Tetrahydrocurcumin, a major curcumin metabolite, exhibits pharmacological activities similar to those of curcumin. Curcumin induces cell death mainly through the apoptosis pathway, and tetrahydrocurcumin induces cell death mainly via an autophagy pathway in HL60 cells. Here, we investigated whether curcumin and tetrahydrocurcumin can induce apoptosis- and autophagy-mediated cell deaths in Ara-C-resistant cancer cells, respectively. The results demonstrated that curcumin and tetrahydrocurcumin induced cell death by apoptosis and autophagy, respectively, in Ara-C-resistant HL60 cells. Thus, curcumin and tetrahydrocurcumin have potential applications in the treatment of acute myeloid leukemia with Ara-C resistance.

Topics: Apoptosis; Autophagy; Cell Death; Curcumin; Female; Humans; Leukemia, Myeloid, Acute; Male

Curcumin, a bioactive compound from turmeric, eliminates cancer stem cells (CSCs) in some cancers. This study evaluates the effects of curcumin on CSC markers in Burkitt lymphoma and acute myeloid leukemia cells.. Cells were treated with increasing concentrations of curcumin, followed by an ALDEFLUOR assay, colony formation assay and western blot analysis for the CSC-associated proteins, Gli-1, Notch-1 and Cyclin D1.. Markers associated with CSCs were decreased in cells treated with curcumin. This included a decrease in the percentage of ALDH-positive cells, a decrease in colony formation and the downregulation of Gli-1, Notch-1 and Cyclin D1.. These results indicate that curcumin decreased CSC markers in lymphoma/leukemia cells, potentially through inhibiting self-renewal.

Topics: Antineoplastic Agents; Biological Products; Biomarkers; Biomarkers, Tumor; Burkitt Lymphoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Signal Transduction; Tumor Stem Cell Assay

Curcumin has been widely used as a food additive for centuries and has been recently explored for its anti-inflammatory and antitumor properties. Although curcumin is pharmacologically safe and efficacious to certain cancers, its role against acute myeloid leukemia (AML) still remains unclear, and it lacks clinical application due to low water solubility and low in vivo bioavailability. To address these issues, we developed a novel curcumin liposome modified with hyaluronan (HA-Cur-LPs) to specifically deliver curcumin to AML by targeting CD44 on AML cell surface. When compared with free curcumin and nontargeted liposome (Cur-LPs), the HA-Cur-LPs exhibited good stability, high affinity to CD44, increased cellular uptake, and more potent activity on inhibiting AML cell proliferation. The KG-1 cell implanted AML mice had significantly delayed, or even prevented, AML progression following treatment with 50 mg/kg of curcumin dose in the HA-Cur-LPs every 2 days for 2 weeks. Mechanistically, the anti-AML effects of HA-Cur-LPs were achieved by inhibiting Akt/ERK pathways and activating caspase-dependent apoptosis. Moreover, HA-Cur-LPs played a critical role in downregulation of DNMT1 expression in AML, leading to DNA hypomethylation and reactivation of tumor suppressor genes such as miR-223. The development and assessment of the HA-Cur-LPs in this study provide another potential choice for AML therapy, using HA-Cur-LPs as either a single treatment agent or in combination with other treatments.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Hyaluronan Receptors; Hyaluronic Acid; Leukemia, Myeloid, Acute; Liposomes; Mice

Fanconi anemia (FA) is an autosomal recessive disorder with a high risk of malignancies including acute myeloid leukemia and squamous cell carcinoma. There is a constant search out of new potential therapeutic molecule to combat this disorder. In most cases, patients with FA develop haematological malignancies with acute myeloid leukemia and acute lymphoblastic leukemia. Identifying drugs which can efficiently block the pathways of both these disorders can be an ideal and novel strategy to treat FA. The curcumin, a natural compound obtained from turmeric is an interesting therapeutic molecule as it has been reported in the literature to combat both FA as well as leukemia. However, its complete mechanism is not elucidated. Herein, a systems biology approach for elucidating the therapeutic potential of curcumin against FA and leukemia is investigated by analyzing the computational molecular interactions of curcumin ligand with FANC G of FA and seven other key disease targets of leukemia. The proteins namely DOT1L, farnesyl transferase (FDPS), histone decetylase (EP3000), Polo-like kinase (PLK-2), aurora-like kinase (AUKRB), tyrosine kinase (ABL1), and retinoic acid receptor alpha (RARA) were chosen as disease targets for leukemia and modeled structure of FANC G protein as the disease target for FA. The docking investigations showed that curcumin had a very high binding affinity of -8.1 kcal/mol with FANC G protein. The key disease targets of leukemia namely tyrosine kinase (ABL1), aurora-like kinase (AUKRB), and polo-like kinase (PLK-2) showed that they had the comparable binding affinities of -9.7 k cal/mol, -8.7 k cal/mol, and -8.6 k cal/mol, respectively with curcumin. Further, the percentage similarity scores obtained from PAM50 using EMBOSS MATCHER was shown to provide a clue to understand the structural relationships to an extent and to predict the binding affinity. This investigation shows that curcumin effectively interacts with the disease targets of both FA and leukemia.

Topics: Computational Biology; Curcumin; DNA-Binding Proteins; Fanconi Anemia; Fanconi Anemia Complementation Group G Protein; Humans; Leukemia, Myeloid, Acute; Ligands; Models, Molecular; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Systems Biology

The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients.. Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method.. Our results suggested that curcumin down regulates MDR genes. Gene expression was decreased by 35.75, 31.30, 27.97 % for MDR1, LRP, BCRP respectively. In FLT3, it was 65.86 % for wild type and 31.79 % for FLT3-ITD. In addition to this, curcumin has also shown anti-proliferative effect as well as synergistic effect in combination with Cytarabine on primary leukemic cells. Thus, we can conclude that curcumin can be used as MDR modulator as well as chemosensitizer in combination with cytarabine, standard chemotherapeutic drug, to reduce the cytotoxicity profile as IC50 value decreases when treated in combination.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Cytarabine; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Neoplasm Proteins; Real-Time Polymerase Chain Reaction; Structure-Activity Relationship; Vault Ribonucleoprotein Particles

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by extremely heterogeneous molecular and biologic abnormalities that hamper the development of effective targeted treatment modalities. While AML cells are highly sensitive to cytotoxic Ca2+ overload, the feasibility of Ca2+- targeted therapy of this disease remains unclear. Here, we show that apoptotic response of AML cells to the synergistically acting polyphenols curcumin (CUR) and carnosic acid (CA), combined at low, non-cytotoxic doses of each compound was mediated solely by disruption of cellular Ca2+ homeostasis. Specifically, activation of caspase cascade in CUR+CA-treated AML cells resulted from sustained elevation of cytosolic Ca2+ (Ca2+cyt) and was not preceded by endoplasmic reticulum stress or mitochondrial damage. The CUR+CA-induced Ca2+cyt rise did not involve excessive influx of extracellular Ca2+ but, rather, occurred due to massive Ca2+ release from intracellular stores concomitant with inhibition of Ca2+cyt extrusion through the plasma membrane. Notably, the CUR+CA combination did not alter Ca2+ homeostasis and viability in non-neoplastic hematopoietic cells, suggesting its cancer-selective action. Most importantly, co-administration of CUR and CA to AML-bearing mice markedly attenuated disease progression in two animal models. Collectively, our results provide the mechanistic and translational basis for further characterization of this combination as a prototype of novel Ca2+-targeted pharmacological tools for the treatment of AML.

Topics: Abietanes; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Calcium; Calcium Signaling; Caspases; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; HL-60 Cells; Homeostasis; Humans; Leukemia, Myeloid, Acute; Mice, Inbred C57BL; Mice, SCID; Time Factors; U937 Cells; Xenograft Model Antitumor Assays

Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.

Topics: Adult; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Curcumin; Etoposide; Female; HL-60 Cells; Humans; Inhibitor of Apoptosis Proteins; Leukemia, Myeloid, Acute; Male; Middle Aged; NF-kappa B; Oxidative Stress; Rats; Rats, Inbred BN; Reactive Oxygen Species; Survivin

Acute myeloid leukemia (AML) initiation and progression have been attributed to subpopulations of self-renewing leukemia stem cells (LSCs), which contribute to progression, recurrence and therapeutic resistance in leukemia. Osteopontin (OPN) plays an important role in promoting survival and drug resistance in LSCs. The aim of this study was to explore OPN roles in modulating curcumin-mediated LSC enrichment and survival in AML cell lines and primary CD34+/CD38- bone-marrow-derived AML cells.. The growth inhibitory effects of curcumin (CUR) were evaluated by MTT assay in U937 and CD34+ KG-1 AML cell lines as well as primary CD34+/CD38- bone-marrow derived AML cells isolated by MACS technique. The proportion of LSC markers (CD34, CD38 and CD123) were evaluated by flow cytometry. The expression levels of OPN, AKT, mTOR, PTEN, β-catenin and NF-κB were investigated by qRT-PCR. Short interfering RNA (siRNA) against OPN was used in AML cells incubated with or without CUR.. Proportions of CD34+/CD38-/CD123+ and CD34+/CD38+/CD123+ LSCs compartment co-expressing an increased level of OPN could be enriched in AML cell lines and in patient's primary cells by CUR treatment. The expression levels of AKT, mTOR, PTEN, and β-catenin and NF-κB1, were also significantly up-regulated concurrently with OPN in the enriched CD34+ AML cells.. The increased in CUR-mediated OPN level is involved in a complex interplay of various signaling pathways resulting in cytoprotection and enrichment of CD34+ LSC compartment in CUR-treated AML cells. AKT/mTOR/PTEN/β-catenin/NF-kB signaling pathways may play roles in modulating OPN-mediated LSC cell survival and enrichment.

Topics: ADP-ribosyl Cyclase 1; Antigens, CD34; Antineoplastic Agents; beta Catenin; Bone Marrow Cells; Cell Line, Tumor; Curcumin; Humans; Interleukin-3 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; NF-kappa B; Oncogene Protein v-akt; Osteopontin; PTEN Phosphohydrolase; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases

To explore the inhibitory effect of curcumin on proliferation of CD34(+) acute myeloid leukemia cells and its mechamism.. KG1a and Kasumi-1cell lines were treated with curcumin of different concentrations (0, 40, 60, 80 µmol/L). The effect of curcumin on cell viability and proliferation was detected by trypan blue staining and cell count. The effect of curcumin on distribution of NF-κB P65 subunit was analyzed by immunofluorescence and Western blot.. The curcumin inhibited proliferation of KG1a and Kasumi-1 cells in a dose-dependent manner. Western blotting showed that curcumin led to significant down-regulation of NF-κB P65 nuclear protein expression. Immunofluorescence assay showed that treatment with 40 µmol/L of curcumin for 48h suppressed the nuclear translocation of NF-κB p65 in KG1a and Kasumi-1 cells.. The curcumin suppresses cell growth of KG1a and Kasumi-1 cells, its mechanism may be related to inhibitory effect of curcumin on NF-κB p65 nucleus protein.

Topics: Antigens, CD34; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Down-Regulation; Humans; Leukemia, Myeloid, Acute; NF-kappa B; Transcription Factor RelA

Acute myeloid leukemia (AML) is a hematological malignancy with a low survival rate. Curcumin, which is a multi-targeted anticancer agent, has been shown to exert anti‑oxidant, anti‑inflammatory, anti‑mutagenic and anti‑carcinogenic activities. Naringenin is extracted from citrus fruits and exerts anti‑mutagenic and anti‑carcinogenic activities in various types of cancer cells. However, the effects of curcumin and naringenin in combination in AML cells have yet to be studied. The present study aimed to investigate the combination effects of curcumin and naringenin on the viability, cell cycle distribution and apoptosis rate of THP‑1 cells using cell viability assays, flow cytometry, and western blotting. Naringenin enhanced curcumin‑induced apoptosis and cell viability inhibition. In addition, curcumin and naringenin induced cell cycle arrest at S phase and G2/M phase. Numerous pathways, including p53, c‑Jun N‑terminal kinases (JNK), Akt and extracellular signal‑regulated kinases (ERK)1/2 pathways were markedly altered following treatment of THP‑1 cells with curcumin and naringenin. These results indicated that naringenin may enhance curcumin‑induced apoptosis through inhibiting the Akt and ERK pathways, and promoting the JNK and p53 pathways.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Extracellular Signal-Regulated MAP Kinases; Flavanones; Humans; Leukemia, Myeloid, Acute; MAP Kinase Kinase 4; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Suppressor Protein p53

Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin.

Topics: Apoptosis; Busulfan; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Drug Synergism; HL-60 Cells; Humans; Inhibitor of Apoptosis Proteins; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Survivin

Leukemia is a hematologic malignancy with a frequent incidence and high mortality rate. Previous studies have shown that the FLT3 gene is overexpressed in leukemic blast cells, especially in acute myeloid leukemia. In this study, a commercially available curcuminoid mixture (1), pure curcumin (2), pure demethoxycurcumin (3), and pure bisdemethoxycurcumin (4) were investigated for their inhibitory effects on cell growth, FLT3 expression, and cell cycle progression in an FLT3-overexpressing EoL-1 leukemic cell line using an MTT assay, Western blotting, and flow cytometry, respectively. The mixture (1) and compounds 2-4 demonstrated cytotoxic effects with IC50 values ranging from 6.5 to 22.5 μM. A significant decrease in FLT3 protein levels was found after curcuminoid treatment with IC20 doses, especially with mixture 1 and compound 2. In addition, mixture 1 and curcumin (2) showed activity on cell cycle arrest at the G0/G1 phase and decreased the FLT3 and STAT5A protein levels in a dose-dependent manner. Compound 2 demonstrated the greatest potential for inhibiting cell growth, cell cycle progression, and FLT3 expression in EoL-1 cells. This investigation has provided new findings regarding the effect of turmeric curcuminoids on FLT3 expression in leukemic cells.

Topics: Cell Cycle Checkpoints; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Molecular Structure

Curcumin is a multi-targeted anti-cancer agent. However, there are few studies on its anti-leukemia activity in human acute monocytic leukemia. Here, we study the effect and mechanisms of curcumin on acute monocytic leukemia.. The acute monocytic leukemia cell line THP-1 was used as in vitro cell model to explore the anti-leukemia effects and mechanisms of curcumin. Cell proliferation was measured by MTT assay, cell apoptosis bodies were observed using a light microscope, cell apoptosis rate was evaluated by flow cytometry, and the expression alterations of growth-sinaling proteins were detected by Western blotting.. Curcumin inhibited cell proliferation and induced cell apoptosis in time- and dose- dependent manner in THP-1 cells. Curcumin significantly inhibited the activations of AKT/mTOR and RAF/MEK/ERK signaling pathways simultaneously.. This study demonstrates that curcumin inhibits proliferation and induces apoptosis in THP-1 cells via inhibiting the activations of AKT/mTOR and RAF/MEK/ERK signaling pathways simultaneously. Our data suggest that curcumin is a promising anti-tumor agent in acute monocytic leukemia.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Coloring Agents; Curcumin; Enzyme Activation; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Leukemia, Myeloid, Acute; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Oncogene Protein v-akt; raf Kinases; Tetrazolium Salts; Thiazoles; TOR Serine-Threonine Kinases

Aberrant expression of forkhead box protein M1 (FoxM1) contributes to carcinogenesis in human cancers, including acute myeloid leukemia (AML), suggesting that the discovery of specific agents targeting FoxM1 would be extremely valuable for the treatment of AML. Curcumin, a naturally occurring phenolic compound, is suggested to possess anti-leukemic activity; however, the underlying mechanism has not been well elucidated. In this study, we found that curcumin inhibited cell survival accompanied by induction of G2/M cell cycle arrest and apoptosis in HL60, Kasumi, NB4, and KG1 cells. This was associated with concomitant attenuation of FoxM1 and its downstream genes, such as cyclin B1, cyclin-dependent kinase (CDK) 2, S-phase kinase-associated protein 2, Cdc25B, survivin, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF), as well as the reduction of the angiogenic effect of AML cells. We also found that specific downregulation of FoxM1 by siRNA prior to curcumin treatment resulted in enhanced cell survival inhibition and induction of apoptosis. Accordingly, FoxM1 siRNA increased the susceptibility of AML cells to doxorubicin-induced apoptosis. More importantly, curcumin suppressed FoxM1 expression, selectively inhibited cell survival as well as the combination of curcumin and doxorubicin exhibited a more inhibitory effect in primary CD34(+) AML cells, while showing limited lethality in normal CD34(+) hematopoietic progenitors. These results identify a novel role for FoxM1 in mediating the biological effects of curcumin in human AML cells. Our data provide the first evidence that curcumin together with chemotherapy or FoxM1 targeting agents may be effective strategies for the treatment of AML.. Curcumin inhibited AML cell survival and angiogenesis and induced chemosensitivity. Aberrant expression of FoxM1 induces AML cell survival and chemoresistance. Inactivation of FoxM1 contributes to curcumin-induced anti-leukemic effects. Curcumin together with FoxM1 targeting agents may be effective for AML therapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Forkhead Box Protein M1; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute

The effect of curcumin, a promising anticancer agent, on the action of certain cytostatic drugs, including etoposide, is not well understood. This paper examines the effect of curcumin on etoposide action in leukemic and normal bone marrow cells in vivo conditions. The experimental model used was Brown Norway rats with a transplantable acute promyelocytic leukemia. Leukemia was induced by intravenous injection of BNML (Brown Norway Myeloid Leukemia) cells. Curcumin was administered by oral gavage (200 mg/kg) for 23 consecutive days and etoposide was used intraperitoneally (50 mg/kg) for the last three days of the experiment. Control leukemic and healthy rats received the solvent for the tested compounds only. Curcumin significantly reduced the number of leukemic promyelocytes in the bone marrow of BNML rats in comparison to the leukemic control. Treatment with curcumin plus etoposide led to a decrease in the number of promyelocytes to the normal values occurring in healthy individuals. In contrast, the percentage of the normal precursors of granulocytes (p <0.001) and erythrocytes (p <0.001) increased significantly in comparison to the group treated with only etoposide. The results of the study indicate that curcumin may protect healthy myeloid cells against the cytotoxic effect of etoposide and potentiate the antileukemic action of this anticancer drug.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bone Marrow; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Etoposide; Leukemia, Myeloid, Acute; Rats; Rats, Inbred BN

Bioactive components from dietary supplements such as curcumin may represent attractive agents for cancer prevention or treatment. DNA methylation plays a critical role in acute myeloid leukemia (AML) development, and presents an excellent target for treatment of this disease. However, it remains largely unknown how curcumin, a component of the popular Indian spice turmeric, plays a role in DNA hypomethylation to reactivate silenced tumor suppressor genes and to present a potential treatment option for AML. Here we show that curcumin down-regulates DNMT1 expression in AML cell lines, both in vitro and in vivo, and in primary AML cells ex vivo. Mechanistically, curcumin reduced the expression of positive regulators of DNMT1, p65 and Sp1, which correlated with a reduction in binding of these transcription factors to the DNMT1 promoter in AML cell lines. This curcumin-mediated down-regulation of DNMT1 expression was concomitant with p15(INK4B) tumor suppressor gene reactivation, hypomethylation of the p15(INK4B) promoter, G1 cell cycle arrest, and induction of tumor cell apoptosis in vitro. In mice implanted with the human AML MV4-11 cell line, administration of curcumin resulted in remarkable suppression of AML tumor growth. Collectively, our data indicate that curcumin shows promise as a potential treatment for AML, and our findings provide a basis for future studies to test the clinical efficacy of curcumin - whether used as a single agent or as an adjuvant - for AML treatment.

Topics: Animals; Antineoplastic Agents; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Down-Regulation; Female; G1 Phase Cell Cycle Checkpoints; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Nude; Promoter Regions, Genetic; Sp1 Transcription Factor; Transcription Factor RelA; Tumor Cells, Cultured

There are contradictory results from studies on the effect of curcumin, a plant phenolic compound with a well-established anticancer effect in vitro, on the action of etoposide in cancer cells.. The aim of this study was to evaluate the influence of curcumin on the genotoxic and cytostatic action of etoposide in the LT12 cell line derived from BN rat acute myeloid leukemia cells.. The LT12 cells were treated with different doses of curcumin for 1-72 hours followed by application of etoposide. The amount of DNA damage was estimated via a comet assay. Viability, cell cycle and apoptosis were examined by using flow cytometry technique.. The combined effect of curcumin and etoposide on viability was synergistic at low micro- molar concentrations. In comparison to treatment with curcumin and etoposide alone, co-treatment with these compounds increased the extent of DNA damage, the percentage of cells arrested in the G2/M phase and the number of annexin-V-positive cells.. The interaction between etoposide and curcumin points to an enhanced antileukemic potential to be derived from the combination of these compounds.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Line, Tumor; Curcumin; DNA Damage; Dose-Response Relationship, Drug; Drug Synergism; Etoposide; Humans; Leukemia, Myeloid, Acute; Mice; Rats

Acute myeloid leukemia (AML) is an immunophenotypically heterogeneous malignant disease, in which CD34 positivity is associated with poor prognosis. CD34+ AML cells are 10-15-fold more resistant to daunorubicin (DNR) than CD34- AML cells. Curcumin is a major component of turmeric that has shown cytotoxic activity in multiple cancers; however, its anti-cancer activity has not been well studied in DNR-insensitive CD34+ AML cells. The aim of this study was to therefore to explore curcumin-induced cytotoxicity in DNR-insensitive CD34+ AML cell lines (KG1a, Kasumi-1), DNR-sensitive U937 AML cells, and primary CD34+ AML bone-marrow-derived cells.. Primary human CD34+ cells were isolated from peripheral blood mononuclear cells or bone marrow mononuclear cells using a CD34 MicroBead kit. The growth inhibitory effects of curcumin were evaluated by MTT and colony-formation assays. Cell cycle distribution was examined by propidium iodide (PI) assay. Apoptosis was analyzed by Wright-Giemsa, Hoechst 33342 and Annexin-V/PI staining assays. The change in mitochondrial membrane potential (MMP) was examined by JC-1 staining and flow cytometry. Expression of apoptosis-related proteins was determined by reverse transcription-polymerase chain reaction and Western blotting. Short interfering RNA (siRNA) against Bcl-2 was used in CD34+ KG1a and Kasumi-1 cells incubated with/without DNR.. Curcumin inhibited proliferation and induced apoptosis and G1/S arrest in both DNR-insensitive KG1a, Kasumi-1 and DNR-sensitive U937 cells. Curcumin-induced apoptosis was associated with reduced expression of both Bcl-2 mRNA and protein, subsequent loss of MMP, and activation of caspase-3 followed by PARP degradation. Curcumin synergistically enhanced the cytotoxic effect of DNR in DNR-insensitive KG1a and Kasumi-1 cells, consistent with decreased Bcl-2 expression. Accordingly, siRNA against Bcl-2 increased the susceptibility of KG1a and Kasumi-1 cells to DNR-induced apoptosis. More importantly, curcumin suppressed Bcl-2 expression, selectively inhibited proliferation and synergistically enhanced the cytotoxicity of DNR in primary CD34+ AML cells, while showing limited lethality in normal CD34+ hematopoietic progenitors.. Curcumin down-regulates Bcl-2 and induces apoptosis in DNR-insensitive CD34+ AML cell lines and primary CD34+ AML cells.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcumin; Daunorubicin; Drug Resistance, Neoplasm; Drug Synergism; Female; G1 Phase; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Male; Membrane Potential, Mitochondrial; Middle Aged; Poly(ADP-ribose) Polymerases; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; RNA, Small Interfering; S Phase

Acute Myeloid Leukemia (AML) accounts for approximately one fifth of all childhood leukemia yet is responsible for a significant proportion of morbidity and mortality in this population. For this reason, research to identify novel targets for the development of effective AML therapeutics has intensified in the recent past. The THP-1 cell line, which was originally established from an infant diagnosed with AML, provides an experimental model for functional, pre-clinical therapeutics and target identification studies of AML. Here we show the expression of the voltage gated potassium channel Kv11.1 in THP-1 cells as opposed to normal hematopoietic stem cells. In addition, curcumin, a natural polyphenol derived from the plant Curcuma longa, effectively blocked Kv11.1 activity and also inhibited the proliferation of these cells. Curcumin was rapidly internalized by THP-1 cells and possibly exerts potential growth inhibitory activity by interacting with intracellular epitopes of the ion channel. Inhibition of ionic currents carried by Kv11.1 resulted in depolarization of cell membrane potential. We propose that the inhibition of Kv11.1 activity by curcumin may lead to interference with leukemic cell physiology and consequently the suppression of survival and proliferation of AML cells.

Topics: Antineoplastic Agents; Cell Line; Cell Proliferation; Curcuma; Curcumin; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Infant; Leukemia, Myeloid, Acute; Membrane Potentials; Potassium; Protein Isoforms

Acute myeloid leukemia (AML) is a malignancy without effective treatment for most patients. Here we demonstrate that combinations of the dietary plant polyphenols--curcumin and carnosic acid--at noncytotoxic concentrations of each agent, produced a synergistic antiproliferative effect and a massive apoptotic cell death in HL-60 and KG-1a human AML cells. In contrast, combinations of curcumin and another plant polyphenol silibinin had a predominantly additive cytostatic effect, without pronounced cytotoxicity. Neither polyphenol combination affected viability of normal human fibroblasts or proliferating and nonproliferating blood cells. Early stage of curcumin/carnosic acid-induced apoptosis was associated with cleavage (activation) of caspase-8, caspase-9, and caspase-3 and the proapoptotic protein Bid, but not with oxidative stress or altered levels of other Bcl-2 family proteins (Bcl-2, Bcl-xl, Mcl-1, Bax, and Bak). Inhibitors of caspase-8 and caspase-9 markedly attenuated apoptosis, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by curcumin + carnosic acid. Collectively, these results suggest a mechanistic basis for the potential use of dietary plant polyphenol combinations in the treatment and prevention of AML.

Topics: Abietanes; Apoptosis; Caspases; Cell Proliferation; Curcumin; Drug Therapy, Combination; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Oligopeptides; Oxidative Stress; Plant Extracts; Silybin; Silymarin

A variety of cancers ectopically express human chorionic gonadotropin beta (hCGbeta). Patients harboring such cancers have poor prognosis and adverse survival. A recombinant chimeric antibody, cPiPP, exhibiting high affinity and specificity for hCGbeta/hCG was engineered. This study was designed to determine whether this antibody alone or conjugated to curcumin can selectively kill tumor cells expressing hCGbeta.. The study was carried out on MOLT-4 and U-937 cells expressing hCGbeta and on peripheral blood leukocytes of acute myeloid leukemia (AML) patients. The anticancerous compound curcumin was conjugated to cPiPP. The binding of cPiPP and cPiPP-curcumin conjugate to cells was studied by flow cytometry and cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), FACS with propidium iodide staining, trypan blue exclusion assay and microscopy.. The antibody did not impair the growth of MOLT-4 and U-937 cells in culture. Its conjugate with curcumin, however, was lethal to both cell lines. The immunoconjugate killed tumor cells bearing the CD33 marker of an AML patient expressing hCGbeta but did not have a similar action on cells of another AML patient with the CD13 marker but who was negative for hCGbeta.. A humanized antibody against hCGbeta linked to curcumin has potential for therapy of hCGbeta-expressing tumors.

Topics: Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Separation; Chorionic Gonadotropin, beta Subunit, Human; Curcumin; Drug Design; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Lymphoma; Male; Middle Aged; Sialic Acid Binding Ig-like Lectin 3; Tetrazolium Salts; Thiazoles; U937 Cells

To investigate whether the Bcl-2 gene family is involved in modulating mechanism of apoptosis and change of cell cycle protein induced by curcumin in acute myeloid leukemia HL-60 cell line and primary acute myelogenous leukemic cells, the Bcl-2 family member Mcl-1, Bax and Bak and cell cycle proteins including P27kipl, P21wafl, cyclin D3 and pRbp- were selected and their expression detected by SABC immuno-histochemical stain method. The attitude of sub-G1 peak in DNA histogram was determined by FCM. The TUNEL positive cell percentage was identified by terminal deoxynucleotidyl transferase (TdT)-mediated Biotin dUNP end labeling technique. It was found that when HL-60 cells were treated with 25 mumol/L curcumin for 24 h, the expression level of Mcl-1 was down-regulated, but that of Bax and Bak up-regulated time-dependently. There was significant difference in the expression level of Mcl-1, Bax and Bak between the curcumin-treated groups and control group (P < 0.05-0.01). At the same time, curcumin had no effect on progress of cell cycle in primaty acute myelogenous leukemia at newly diagnosis, but could increase the peak of Sub-G1 (P < 0.05), and down-regulate the expression of Mcl-1 and up-regulate the expression of Bax and Bak with the difference being statistically significant. The expression of P27kipl, P21wafl and pRbp- were elevated and that of cyclin D3 decreased in the presence of curcumin. These findings suggested that the Bcl-2 gene family indeed participated in the regulatory process of apoptosis induced by curcumin in HL-60 cells and AML cells. Curcumin can induce apoptosis of primary acute myelogenous leukemic cells and disturb cell cycle progression of HL-60 cells. The mechanism appeared to be mediated by perturbing G0/G1 phases checkpoints which associated with up-regulation of P27kipl, P21wafl and pRbp- expression, and down-regulation of cyclin D3.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Cell Cycle Proteins; Curcumin; Genes, bcl-2; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured