A novel necroptosis-related gene signature in acute myeloid leukemia.

OBJECTIVE: Necroptosis has been reported to play an important role in different cancers, including leukemia. However, biomarkers of necroptosis-related genes (NRGs) that help predict the prognosis of AML are still lacking. Our research aims to build a novel signature of NRGs that could enhance our understanding of the molecular heterogeneity in leukemia. METHOD: Gene expression profiles as well as clinical features were downloaded from TCGA and GEO databases. Data analysis were executed using R software version 4.2.1 and GraphPad Prism version 9.0.0. RESULT: Univariate cox regression and lasso regression were applied to identify survival-specific genes. Four genes including FADD, PLA2G4A, PYCARD and ZBP1 were considered as independent risk factors that affect the prognosis of patients. Risk scores were calculated according to the coefficient of four genes. Then clinical characteristics and risk scores were enrolled to construct a nomogram. CellMiner was also used to screen potential drugs and analyze the correlations between genes and drug sensitivity. CONCLUSION: In general, we established a signature of four genes related to necroptosis that could be helpful for future risk stratification in patients with AML.

Retrospective Study of Three Cases of Congenital Leukemia with Clinical Presentations and Particular Cytogenetic Abnormality.

BACKGROUND: The goal is to assess the prognosis of cytogenetic abnormality, because cytogenetic abnormality is rarely encountered in clinical practice. METHODS: We retrospectively report three cytogenetic abnormality cases with clinical, cytogenetic, and genetic characteristic. RESULTS: All cases occurred within one month of birth and had prominent hepatosplenomegaly, including acute myeloid leukemia (case 1, case 2) and acute leukemia (case 3). Moreover, case 1 appeared as leukemia cutis at birth, case 2 was born with respiratory distress, and both showed hyperleukocytosis. The R-banded karyotype detected cytogenetic abnormality in three cases, case 1 with 46,XY,t(8;12)(q21;p13), case 2 with 47,XX,+21 and case 3 with 46,XY,t(6;X)(q22:p12), respectively. Especially in case 1, reverse transcription-polymerase chain reaction analysis showed MLL-AF10 rearranged. CONCLUSIONS: In our studies, all cases had not received chemotherapy and survived about 1 - 2 months. It suggests that cytogenetic disorders are closely related to disease development and likely result in fatal outcome if untreated. Thus, we proposed that a proper treatment decision is urgently needed in congenital leukemia.

Evidence for ABL Amplification in Multiple Myeloma and Therapeutic Implications.

Background: Cytogenetic abnormalities are considered initiating events in the pathogenesis of multiple myeloma (MM) and are assumed to be of clinical significance. Methods: Fluorescence in situ hybridization (FISH) was used to analyze chromosomal architecture in 101 patients with MM. We evaluated overall patient survival and assessed the cytotoxicity of imatinib against MM cells using a CCK8 assay. Results: ABL gene amplification was detected in 67 patients (66.3%). However, ABL gene amplification was not associated with clinical features, cytogenetic abnormalities (c-Myc amplification, IGH rearrangement, RB1 deletion, p53 deletion, or 1q21 amplification), or overall survival. ABL amplification in MM cell lines (LP-1 and U266) was revealed by FISH. Furthermore, the ABL protein was easily detectable in MM cell lines and some tumor cells by western blotting. A CCK8 assay indicated limited cytotoxicity of imatinib against MM cells. Conclusions: Our study firstly discussed ABL gene amplification was prevalent in MM cells, and we believe that the ABL gene would potentially be a useful target in the treatment of combination strategy for MM with ABL amplification in the future.

Isochromosome 11q is Associated with Unique Characteristics and Poor Prognosis in Patients with Acute Myeloid Leukemia.

BACKGROUND: Isochromosome 11q in patients with acute myeloid leukemia is rarely reported, and little is known about its main features. METHODS: The presence of isochromosome 11q was identified in four patients (three adults and one child) from screening 441 patients with an acute myeloid leukemia diagnosis between 2009 and 2018 by using R-banding and fluorescence in situ hybridization. RESULTS: The child, patient 1 with unreported isochromosome (partial 11q isochromosome), accompanied with t(1;11) translocation, initially achieved remission after receiving chemotherapy. However, 4 months later this patient experienced a relapse. While multiple treatments were tried, it had no effect and the patient survived for 16 months. The remaining patients with isochromosome 11q exhibited numerical/structural chromosomal abnormal-ities involving myelodysplastic syndrome-related chromosomes 5, 7, 8, and 20. In patients 2 and 3, we found a derivative chromosome 21. Patient 3 was newly diagnosed with acute myeloid leukemia and was treated with many chemotherapy protocols, unfortunately with no effect. The patient then received traditional Chinese medicine and survived for 10 months, although she still has not achieved complete remission. Patients 2 and 4 received chemotherapy but experienced rapid disease progression and died within 2 months. CONCLUSIONS: In summary, patients with isochromosome 11q/partial 11q isochromosome have a poorer prognosis, especially for isochromosome 11q. Furthermore, these chromosome aberrations may be risk factors for the presence of isochromosome 11q or myelodysplastic syndrome-related genes, both of them may be associated with a failure to respond to treatment and poor outcomes. Hence, these discoveries may lay a foundation to study mechanisms and explore treatments.

Novel SAHA­bendamustine hybrid NL­101 in combination with daunorubicin synergistically suppresses acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly aggressive disease with high mortality and recurrence rates, for which novel therapeutic approaches are required. Hybrid anticancer agents with dual effects have been reported to possess therapeutic potential to treat AML. However, the efficacy and underlying toxicity of these hybrids in combination with other agents remain unclear. NL­101 is a novel hybrid formed by fusing the DNA damage­inducing agent bendamustine with the histone deacetylase inhibitor vorinostat. In the present study, NL­101 treatment was combined with the conventional chemotherapeutic drug daunorubicin (DNR) in AML cells, and it was revealed that these two compounds exerted synergistic anti­AML effects. In addition, NL­101 enhanced DNR­induced cell apoptosis, as assessed by flow cytometry and as indicated by the upregulation of cleaved­poly (ADP­ribose) polymerase, cleaved­caspase­3, cleaved­caspase­7, BAD and BIM. Mechanistically, the DNA double­strand breaks marker γ­H2AX, and other proteins associated with DNA damage, were investigated, and it was demonstrated that NL­101 in combination with DNR synergistically promoted the DNA damage response. In vivo, this combination significantly delayed the progression of AML and prolonged the survival time in mice. Collectively, the present results suggested that NL­101 in combination with daunorubicin could be an alternative novel therapeutic strategy for treating leukemia.

Bioinformatics analysis of the network of histone H3 lysine 9 trimethylation in acute myeloid leukaemia.

Changes in histone H3 lysine 9 trimethylation (H3K9me3) may be related to the development of drug­resistant acute myeloid leukaemia (AML); insights into the network of H3K9me3 may improve patient prognosis. Patient data were derived from the Gene Expression Omnibus (GEO) database and data from AML cells treated with chidamide, a novel benzamide chemical class of histone deacetylase inhibitor (HDACi), in vitro were derived from ChIP­seq. Patients and AML cell data were analysed using GEO2R, GOseq, KOBAS, the STRING database and Cytoscape 3.5.1. We identified several genes related to the upregulation or downregulation of H3K9me3 in AML patients; some of these genes were related to apoptosis, autophagy, and the pathway of cell longevity. AML cells treated with chidamide in vitro showed the same gene changes. The protein interactions in the network did not have significantly more interactions than expected, suggesting the need for more research to identify these interactions. One compelling result from the protein interaction study was that sirtuin 1 (SIRT1) may have an indirect interaction with lysine­specific demethylase 4A (KDM4A). These results help explain alterations of H3K9me3 in AML that may direct further studies aimed at improving patient prognosis. These results may also provide a basis for chidamide as a treatment strategy for AML patients in the future.

Chidamide Enhances the Cytotoxicity of Cytarabine and Sorafenib in Acute Myeloid Leukemia Cells by Modulating H3K9me3 and Autophagy Levels.

Previous studies showed that chidamide enhances the cytotoxicity of drugs in acute myeloid leukemia (AML) cells. Therefore, we examined whether chidamide enhanced the cytotoxicity of drugs in AML cells by affecting H3K9me3 and autophagy levels. AML cells (THP-1 and MV4-11 cells) were treated with chidamide, cytarabine (Ara-c), or sorafenib alone or in combination. Cell proliferation and survival rates were analyzed by MTT, flow cytometry, and Western blotting assays. The results showed that a low dose of chidamide enhanced the cytotoxicity of Ara-c or sorafenib in AML cells, decreasing proliferation and increasing apoptosis. H3K9me3 levels as assessed by Western blotting were upregulated by chidamide treatment. Chromatin immunoprecipitation sequencing, which was used to investigate potential signaling pathways, indicated that the autophagy pathway might play a role in the effects of chidamide. The level of autophagy induced in AML cells upon treatment with Ara-c or sorafenib was inhibited by chidamide, and autophagy markers (LC3, P62) were tested by Western blotting. SIRT1 messenger RNA (mRNA) and protein levels were lower in AML cells treated with Ara-c or sorafenib in combination with chidamide than those in cells treated with these drugs alone. Additionally, the Integrative Genomics Viewer results indicate that the H3K9me3 changes were related to SIRT1-binding sites. Together, these results show that chidamide enhances the cytotoxicity of two chemotherapy drugs in AML cells by increasing the H3K9me3 level and inhibiting autophagy via decreasing the expression of SIRT1. Chidamide may be a potential treatment strategy for AML in the future, especially for refractory AML patients.

Once-weekly bortezomib had similar effectiveness and lower thrombocytopenia occurrence compared with twice-weekly bortezomib regimen in treating patients with newly diagnosed multiple myeloma in China.

The study aims to examine the treatment effect and adverse reactions of patients with newly diagnosed MM receiving different bortezomib-based regimens.This was a retrospective study of patients with newly diagnosed MM and who were treated with bortezomib-based combined chemotherapy at the Department of Hematology of the 2 affiliated hospitals of Wenzhou Medical University between July 2009 and May 2016. Cox proportion hazard multivariate analyses were carried out to assess the differences in treatment effect and adverse events between standard (1.3 mg/m on days 1, 4, 8, 11) and weekly (1.6 mg/m on days 1, 8, 15) cohorts, as well as the differences between intravenous injection and subcutaneous injection therapy. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test.Among the 117 patients, 78 patients were treated with bortezomib standard therapy and 39 patients were treated with bortezomib weekly therapy (all with intravenous injection). In all patients, the treatment strategy was not independently associated with PFS or OS. The patients in the weekly therapy group had less thrombocytopenia events than those in the standard therapy group. The subcutaneous route had similar treatment effect as the intravenous route, but the incidence of peripheral neuropathy was lower.The once-weekly bortezomib regimen was similar in effectiveness to standard therapy in treating patients with newly diagnosed MM, but the incidence of thrombocytopenia was lower with the weekly regimen compared with the standard regimen.

A novel alkylating deacetylase inhibitor molecule EDO-S101 in combination with cytarabine synergistically enhances apoptosis of acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a devastating disease. Hybrid agents with dual activity, which have been shown to possess anti-cancer effect, are expected to potentially improve the prognosis of AML patients. EDO-S101 is a novel alkylating deacetylase inhibitor molecule synthesized by the addition of the hydroxamic acid of histone deacetylases inhibitor vorinostat into bendamustine, a DNA-damaging agent. However, the effect of EDO-S101 in combination with traditional chemotherapy drugs has not been studied in AML. In this study, we investigated the effect of EDO-S101 in combination with cytarabine in treating AML cells. The synergic activity against AML was identified by remarkable reduction of cell viability, significant apoptosis enhancement and the upregulation of the cleaved PARP, Casepase-3 and -7 proteins compared with monotherapy. To explain the drivers, we detected the DNA damage pathway including DNA double-strand breaks marker γ-H2AX and DNA damage checkpoint proteins, which was supposed to be responsible for the enhanced apoptosis activity. In summary, our data demonstrated that EDO-S101 in combination with cytarabine could synergistically induce the apoptosis of AML cells and it might be a potential regimen for treating leukemia.

Down-regulated miR-148b increases resistance to CHOP in diffuse large B-cell lymphoma cells by rescuing Ezrin.

BACKGROUND: Aberrant microRNA (miRNAs) have recently been proposed as important regulators in acquiring resistance to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to establish the role of miR-148b in the development of CHOP resistance in DLBCL. METHODS: The expression patterns of miR-148b, HDAC6, and Ezrin were detected in CHOP-resistant clinical specimens and a DLBCL cell line. miR-148b, HDAC6, and Ezrin in DLBCL cells were manipulated by cell transfection to explore the functional correlation between them. Cell viability was determined using a CCK-8 assay. RESULTS: We found that miR-148b levels were markedly reduced and that the protein expressions of HDAC6 and Ezrin were increased in DLBCL CHOP-resistant clinical specimens and the cell line CRL2631/CHOP. Indeed, HDAC6 decreased the acetylation of histones H3 and H4 in the miR-148b promoter to inhibit miR-148b expression in DLBCL. Moreover, down-regulated miR-148b encouraged CHOP resistance in CRL2631 cells and miR-148b sensitized CRL2631 cells. We further revealed that Ezrin was negatively regulated by miR-148b and that the knockdown of Ezrin significantly attenuated CHOP resistance in CRL2631 cells induced by miR-148b silencing. MiR-148b also sensitized CRL2631/CHOP cell xenografts to CHOP in mice. CONCLUSION: Our data indicated that the high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.

The change of nuclear LC3 distribution in acute myeloid leukemia cells.

Making sure the change of nuclear LC3 distribution in the autophagy of acute myeloid leukemia (AML) cell and finding out the regulation mechanism may lead to a breakthrough for killing AML cells. Western blots were performed to assess the expression of autophagy proteins. Changes in the LC3 distribution were monitored by immunofluorescence assays together with western blots, and the expression levels of Sirt1, DOR, Beclin1, HMGB1, and AMPK mRNA were detected via fluorescent quantitative PCR. The effects of Sirt1 and DOR on cell proliferation and survival were analyzed by MTT, flow cytometry, and western blotting assays. We found that treating AML cells with Ara-c or Sorafenib resulted in autophagy enhancement, and when autophagy was enhanced, nuclear LC3 moved into the cytoplasm. Notably, when autophagy was inhibited by blocking the nuclear LC3 shift, the cytotoxicity of drugs was enhanced. Our results also identified Sirt1 and DOR as regulatory molecules for the observed nuclear LC3 shift, and these molecules further affected the expression of Beclin1, HMGB1, and AMPK. Our results suggest the distribution of nuclear LC3 can be a novel way for further studying death of AML cells,and the regulatory molecules may be new targets for treating AML.

LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma.

Multiple myeloma (MM), the second most common hematologic malignancy, is an incurable disease characterized by the accumulation of malignant plasma cells within the bone marrow. Though great progresses have been made in understanding the mechanisms of MM, metabolic plasticity and drug resistance remain largely unknown. In this study, we found lncRNA Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is highly expressed in MM and is associated with the survival rate of MM patients. PDIA3P regulates MM growth and drug resistance through Glucose 6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Mechanistically, we revealed that PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, stimulating G6PD expression and PPP flux. Our study identified PDIA3P as a novel c-Myc interacting lncRNA and elucidated crucial roles for PDIA3P in metabolic regulation of MM, providing a potential therapeutic target for MM patients.

Increased histone deacetylase 6 expression serves as a favorable prognostic factor for diffuse large B-cell lymphoma.

OBJECTIVE: This study aims to investigate ectopic expression of histone deacetylase 6 (HDAC6) in diffuse large B-cell lymphoma (DLBCL). METHODS: This study analyzed patients with DLBCL (n=132) and reactive lymph node hyperplasia (n=32) diagnosed in our hospital from December 2007 to May 2016. Correlation between HDAC6 expression and clinical pathologic features was analyzed by χ2 test. The significant differences between the 5-year overall survival (OS) or progression-free survival (PFS) and high HDAC6 expression as well as DLBCL clinic-pathological features including age, International Prognostic Index (IPI) score, Eastern Cooperative Oncology Group score, lactate dehydrogenase (LDH), and germinal center B-cell-like were assessed by univariate and multivariate analyses. RESULTS: HDAC6 high-expression percentage in DLBCL was significantly higher than that in the control group. The proportion of IPI score of 0-2, 5-year OS, and PFS in the high-expression group, which had lower percentage of patients with increased LDH and ß2-microglobulin, were significantly higher than those in the low-expression group. Moreover, HDAC6 mRNA expression in HDAC6 protein low expression was markedly lower than that in protein high expression. The multivariate analysis demonstrated that HDAC6 high expression was an independent prognostic factor for patients with DLBCL. CONCLUSION: HDAC6 high expression might be a prognostic factor for DLBCL.

Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine.

Chidamide, a novel histone deacetylase inhibitor (HDACi), has been approved for treatment of T-cell lymphomas in multiple clinical trials. It has been demonstrated that chidamide can inhibit cell cycle, promote apoptosis and induce differentiation in leukemia cells, whereas its effect on acute myeloid leukemia (AML) patients with FLT3-ITD mutation has not been clarified. In this study, we found that chidamide specifically induced G0/G1 arrest and apoptosis in FLT3-ITD positive AML cells in a concentration and time-dependent manner. We also found chidamide had the cytotoxicity effect on FLT3-ITD positive and negative AML cells. Moreover, with respect to relapsed/refractory patients, chidamide showed the same effectiveness as that in de novo AML patients. Notably, chidamide synergistically enhanced apoptosis caused by cytarabine. Our results support chidamide alone or combine with cytarabine may be used as an alternative therapeutic choice for AML patients especially those with FLT3-ITD mutation or relapsed/refractory ones.

[Advances Research on C-MYC Proto-oncogene in Multiple Myeloma -Review].

Multiple myeloma(MM) as one of the most common tumors of hmatologic system, is characterized by malignant proliferation of plasma cells, and the chemotherapy is the main therapeutic method. MM is an incurable disease because of drug-resistance of MM cells. Although the pathogenesis of MM remains unknown, the chromosome abnormalities exit in half of the patients, particularly the highly expressed gene C-MYC. Furthermore, plenty of clinical researches indicated a high expression level of C-MYC implied worse progression and/or poor prognosis of MM. Recently, the work exploiting the compounds targeting MYC has made substantial progress, even in the MM therapy. In this article, briefly the recent advances of the research on C-MYC proto-oncogene in multiple myeloma are reviewed.

A Meta-Analysis for Effects of Elevated Pre-Transplantation Serum Ferritin on the Outcomes in Patients Undergoing Hematopoietic Stem Cell Transplantation.

The level of pre-transplantation serum ferritin (SF) is one of the factors related to outcome for patients undergoing allogeneic hematopoietic stem cell transplantation. We searched PubMed and Cochrane Library databases from 2000 to 2014. The primary efficacy outcome was overall survival rate and non-relapse mortality. Twenty clinical trials were selected from 189 studies identified. The combined hazard ratio indicated a significantly lower overall survival rate and a higher non-relapse mortality rate in patients with elevated SF before transplantation. This indicates that elevated pre-transplantation SF affects outcome in patients undergoing allogeneic hematopoietic stem cell transplantation.

Role of caspase-10 in the death of acute leukemia cells.

Autophagy can protect cells from stress, but can also induce cancer cell death. Caspase-10 is now considered to be a factor that is associated with autophagy in cancer. The present study therefore investigated whether caspase-10 affects autophagy in acute leukemia cells. The rates of survival vs. apoptosis in acute leukemia HL-60 and Jurkat cells treated with drugs were tested using cell viability assays and flow cytometry, and the levels of caspase-3 and -10 were tested by western blotting. In HL-60 cells that were treated with chemotherapy drugs combined with a caspase-10 inhibitor, the rate of survival decreased significantly compared with HL-60 cells treated with chemotherapy drugs alone. In contrast, the rate of survival of Jurkat cells treated with chemotherapy drugs combined with the caspase-10 inhibitor increased significantly compared with Jurkat cells treated with chemotherapy drugs alone. The results of the flow cytometry and western blotting showed that the changes in the survival rate may be caused by a change in the amount of apoptosis occurring in the Jurkat cells treated with chemotherapy drugs combined with the caspase-10 inhibitor. However, in HL-60 cells undergoing this combination treatment, the change in the survival rate was not caused by a change in the rate of apoptosis. When HL-60 cells were treated with the chemotherapy drugs combined with the caspase-10 inhibitor and the autophagy inhibitor 3-methyl adenine, the survival rate increased, whereas the rate of apoptosis did not change. These results show that caspase-10 may be associated with autophagy in acute myeloid leukemia cells, but not in acute lymphatic leukemia cells.

Expression of AQP1 Was Associated with Apoptosis and Survival of Patients in Gastric Adenocarcinoma.

RATIONALE AND OBJECTIVE: Recently, interest in the role of aquaporin 1 (AQP1) in human gastrointestinal carcinogenesis has developed. However, to date no studies have examined relationships between AQP1 expression and specific characteristics of gastric adenocarcinoma. METHODS: We investigated 109 specimens of primary gastric adenocarcinoma and their corresponding normal gastric mucosa using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to determine AQP1 expression. We then evaluated disease free survival (DFS) and overall survival (OS) in these patients in association with AQP1 expression. RESULTS: Both immunohistochemical and RT-PCR analyses identified increased AQP1 expression in tumors from patients with gastric adenocarcinoma (p < 0.001). The 3-year DFS and OS rates were higher in the AQP1-negative group than in the positive group (DFS: 77.2 vs. 52.8%, p < 0.001; OS: 85.1 vs. 70.7%, p < 0.001). The 5-year DFS and OS rates exhibited a similar trend (p < 0.001). Subgroup analysis of patients with early gastric adenocarcinoma (stages I and II) revealed a total 5-year OS of 90.0%, with 5-year OS being higher in the AQP1-negative group than in the positive group (95.2 vs. 84.2%). Furthermore, incidence of tumor recurrence following surgical treatment was significantly higher in the AQP1-positive group (4/19, 21.1%) compared with the negative group (0/21, 0%). CONCLUSIONS: Our study demonstrates that AQP1 plays an important role in gastric adenocarcinoma and may therefore represent a novel therapeutic target and prognostic marker in this disease.

CD1d levels in peripheral blood of patients with acute myeloid leukemia and acute lymphoblastic leukemia.

The antitumor effect of natural killer T cells has been reported in several studies analyzing the expression of CD1d on antigen-presenting cells (APCs). Therefore, the present study questioned whether APCs may be abnormal in the peripheral blood (PB) of acute leukemia (AL) patients, particularly the levels of CD1d. To improve the understanding of the role of CD1d on APCs, the levels of CD1d on monocytes were analyzed in healthy controls, AL patients and AL patients with complete remission (CR). In addition, the correlation between the number of CD3+CD56+ T lymphocytes and levels of CD1d on monocytes was analyzed. Flow cytometry was used to determine the levels of CD1d on monocytes and lymphocytes. A significant decrease was observed in the levels of CD1d on monocytes in the PB of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients compared with the healthy controls. Simultaneously, significantly different levels of CD1d on monocytes were identified between the CR-AML and the CR-ALL patients; the levels of CD1d on monocytes remained low in the CR-AML patients, while the levels of CD1d on monocytes recovered in the CR-ALL patients. A significantly negative correlation was observed between the number of CD3+CD56+ T lymphocytes and the levels of CD1d on monocytes in AL patients. However, a significantly positive correlation was identified between the cytotoxicity of the CD3+CD56+ T lymphocytes and the levels of CD1d on monocytes. These results suggested that the significantly low levels of CD1d on monocytes may contribute to AML and ALL progression. In addition, a significant correlation was observed between the levels of CD1d on monocytes and the number/cytotoxicity of CD3+CD56+ T lymphocytes in AML and ALL patients.

Synthesis and in vitro biological evaluation of hybrids from tetrahydro-ß-carboline and hydroxylcinnamic acid as antitumor carcinoma agents.

Novel hybrids 8a-j and 9a-j were designed and synthesized by coupling the carboxyl group of hydroxylcinnamic acids with tetrahydro-ß-carboline alkaloids which were linked with different substituted nitrogen-containing heterocycles at the positions-N9, and their in vitro biological activities were evaluated. It was found that most hybrids showed good to moderate anti-tumor activities. Especially, compound 9j had a great potency superior to 5-fluorouracil (5-FU) and comparable to adriamycin in human cancer cells, and could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. More importantly, apoptosis assay indicated that 9j could significantly induce tumor cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new hybrids for the intervention of human cancers.