Leukemia

My Sunshine Boy

by Reuben Wong

'Father and baby' column published in 'Mother and Baby' (Singapore, May 2012), p.74.

Reflections on coping with and growing up with Down Syndrome in Singapore. Reflections on coping with and growing up with Down Syndrome in Singapore.

Epigenomics of leukemia: from mechanisms to therapeutic applications

by Cristina Florean

Leukemogenesis is a multistep process in which successive transformational events enhance the ability of a clonal... more Leukemogenesis is a multistep process in which successive transformational events enhance the ability of a clonal population arising from hematopoietic progenitor cells to proliferate, differentiate and survive. Clinically and pathologically, leukemia is subdivided into four main categories: chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia. Leukemia has been previously considered only as a genetic disease. However, in recent years, significant advances have been made in the elucidation of the leukemogenesis-associated processes. Thus, we have come to understand that epigenetic alterations including DNA methylation, histone modifications and miRNA are involved in the permanent changes of gene expression controlling the leukemia phenotype. In this article, we will focus on the epigenetic defects associated with leukemia and their implications as biomarkers for diagnostic, prognostic and therapeutic applications.

Design and Synthesis of Thiadiazoles and Thiazoles Targeting the Bcr-Abl T315I Mutant: from Docking False Positives to ATP-Noncompetitive Inhibitors

by Marco Radi

In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and... more In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and 1,3-thiazoles were designed and synthesized, paying particular attention to the reduction of their lipophilicity and to the improvement of the affinity towards the drug-resistant T315I mutant. Compound 5 was identified as a promising allosteric inhibitor of the T315I mutant.

Identification and characterization of novel c-Abl / c-Src dual kinase inhibitors which are active against a large panel of tumour progenitor cells that express stem cell marker

by Marco Radi

Background

The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human... more Background

The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs.

Methodology/Principal Findings

Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK) signalling to impact cytoskeleton dynamics, migration, invasion and metastasis.

Conclusions/Significance

Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

New insight into small molecules inhibitors of Bcr-Abl

by Marco Radi

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the... more Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

Simultaneous Inhibition of SRC and STAT3 Induces an Apoptotic Response in Prostate Cancer Cells

by Ravi Dinakar

*For the FREE full text of this article, visit www.jes2s.com/pdfs/src.pdf

Authors:

Sherman Leung1,3, Elizabeth Duval2, and Olga Timofeeva4
Student1, Teacher2: Science, Mathematics, and Computer Science Magnet Program, Montgomery Blair High School
51 East Boulevard, Silver Spring, MD, 20901
Intern3, Mentor/Assistant Professor4: Lombardi Comprehensive Cancer Center, Georgetown University
3800 Reservoir Road, N.W. Washington, DC 20007

Prostate cancer is the most frequently diagnosed
non-cutaneous cancer and the second leading
cause of... more Prostate cancer is the most frequently diagnosed
non-cutaneous cancer and the second leading
cause of cancer-related deaths in American men.
Recent studies have suggested that sarcoma
inducing kinase (SRC) and its downstream
signaling targets are implicated in prostate cancer,
but the mechanisms behind how SRC inhibition
induces apoptosis are still poorly understood.
This study focused specifically on the interactions
between SRC and its one of its downstream targets,
Signal transducer and activator of transcription
3 (STAT3), in prostate cancer cells. Contrary to
studies on the SRC/STAT3 pathway, western
blotting showed that SRC inhibition had minimal
effects on phosphorlyated-STAT3 levels in DU145
prostate cancer cells. Simultaneous inhibition of
both SRC and STAT3 through PP2 (inhibits SRC
expression) and STAT3 siRNA, respectively, led
to more distinct poly (ADP-ribose) polymerase
1 (PARP-1) cleavage, a hallmark indicator of
apoptosis. qRT-PCR analysis showed a two-fold
and three-fold decrease between simultaneous
versus exclusive treatments in levels of induced
myeloid cell leukemia (MCL-1), a pro-survival
gene. Together, these findings suggest that the
inhibition of STAT3 through SRC is ineffective and
that the independent inhibition of STAT3 induces
a stronger apoptotic response. Additionally, the
study suggests that the simultaneous inhibition of
SRC and STAT3 may be a novel and promising
treatment for prostate cancer.

Typhonium flagelliforme inhibits the proliferation of murine leukemia WEHI-3 cells in vitro and induces apoptosis in vivo

by Dr Syam Mohan

Zerumbone induces apoptosis in T-acute lymphoblastic leukemia cells

by Dr Syam Mohan

Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this... more Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC(50) of 8.4 ± 1.9 μg/ml (coefficient of variation < 30%). Comparatively, 5-fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC(50) of 1.94 ± 0.06 μg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia.

Alterations of bone mineral metabolism of children with different cell lineage types of acute lymphoblastic leukaemia under chemotherapy.

by Charalampos Dokos

Published in Hippokratia

Background: Children with haematological malignancies such as acute lymphoblastic leukaemia (ALL) may have... more Background: Children with haematological malignancies such as acute lymphoblastic leukaemia (ALL) may have alteration
of bone mineral metabolism therefore increased risk for osteopenia and osteoporosis.
Patients and Methods: The purpose of this study was to examine the alterations of bone mineral metabolism in two
groups of children (n=42) according to immunophenotyping (B-cell type, T-cell type) both quantitative (bone mineral
density z-scores) and qualitative (serum osteocalcin - OC and carboxyl-terminal telopeptide of human type I collagen
- ICTP) during diagnosis (T=0), after the intensified chemotherapy period (T=0.5) and the consolidation period (T=1).
Results: According to our results 15 patients had osteopenia and 1 child developed osteoporosis at T=0.5 and 13 patients
had osteopenia at T=1. Mean BMD z-score was significantly decreased in both groups during chemotherapy and especially
statistically significant decline of T-cell type ALL group compared with B-cell type ALL patients. OC mean level
remains in low levels for both groups reaching in plateau during chemotherapy and ICTP level was increased in T-cell
type ALL group of patients compared with B-cell type in both periods of chemotherapy.
Conclusions: It seems that not only the combination of chemotherapeutic agents but also the cell lineage of ALL are
important parameters of altering bone mineral metabolism.

The Transcriptional Network That Controls Growth Arrest and Differentiation In a Human Myeloid Leukemia Cell Line

by Anthony Beckhouse

Images in Medical Practice

by Md. Shahriar Mahbub

Journal of Bangladesh College of Physicians and Surgeons Vol 28, No 3 (2010)

Toward the development of bifunctional agents to induce differentiation and promote apoptosis in leukemia: Overview and perspectives

by Maria Chatzopoulou

Authors: Vizirianakis, I.S.*; Chatzopoulou, M.; Bonovolias, I.; Nicolaou, I.; Demopoulos, V.J.; Tsiftsoglou, A.S;

Citation: J. Med. Chem. 63: 6779-6810 (2010)

Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro

by Sabya Biswas

Leuk Res. 2010 Jul;34(7):925-31. Epub 2010 Feb 19.
Sabyasachi Biswas, Xiaobin B. Zhao, Andrew P. Mone, Xiaokui Mo, Melissa Vargo, David Jarjoura, John C. Byrd, Natarajan Muthusamy