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Wednesday, November 2, 2016
Highlighted Article: Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening
Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening
Author(s):
Amit Sharma, Nidhi Jyotsana, Courteney K. Lai, Anuhar Chaturvedi, Razif Gabdoulline, Kerstin Görlich, Cecilia Murphy, Jan E. Blanchard, Arnold Ganser, Eric Brown, John A. Hassell, R. Keith Humphries, Michael Morgan and Michael Heuser Pages 818 - 828 ( 11 )
Abstract:
Hematopoietic stem and progenitor cell differentiation are blocked in acute myeloid leukemia (AML) resulting in cytopenias and a high risk of death. Most patients with AML become resistant to treatment due to lack of effective cytotoxic and differentiation promoting compounds. High MN1 expression confers poor prognosis to AML patients and induces resistance to cytarabine and alltrans-retinoic acid (ATRA) induced differentiation. Using a high-throughput drug screening, we identified the dihydrofolate reductase (DHFR) antagonist pyrimethamine to be a potent inducer of apoptosis and differentiation in several murine and human leukemia cell lines. Oral pyrimethamine treatment was effective in two xenograft mouse models and specifically targeted leukemic cells in human AML cell lines and primary patient cells, while CD34+ cells from healthy donors were unaffected. The antileukemic effects of PMT could be partially rescued by excess folic acid, suggesting an oncogenic function of folate metabolism in AML. Thus, our study identifies pyrimethamine as a candidate drug that should be further evaluated in AML treatment.
Keywords:
AML, apoptosis, differentiation and DHFR, High-throughput drug screening.
Affiliation:
Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Graphical Abstract:
For More Information Please Visit Our Website Current Cancer Drug Targets
Monday, October 24, 2016
Most Cited Article: Cytochromes P450 and Skin Cancer: Role of Local Endocrine Pathways
Cytochromes P450 and Skin Cancer:
Role of Local Endocrine Pathways
Author(s):
Andrzej T. Slominski, Michal A. Zmijewski, Igor Semak, Blazej
Zbytek, Alexander Pisarchik, Wei Li, Jordan Zjawiony and Robert C. TuckeyPages
77-96 (20)
Abstract:
Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7- steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.
Keywords:
CYP, melatonin, secosteroids, skin cancer, steroids, vitamin D.
Affiliation:
Department of Pathology and Laboratory Medicine, University of
Tennessee Health Science Center, 930 Madison Avenue, RM525, Memphis, TN 38163.
For More Information Please Visit Our Website Recent Patents on Anti-Cancer Drug
Tuesday, October 18, 2016
Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer
Article Details
Advances in Synergistic Combinations of Chinese Herbal Medicine
for the Treatment of Cancer
Author(s):
Xue-Qing Hu, Yang Sun, Eric Lau,
Ming Zhao and Shi-Bing SuPages 346-356 (11)
Abstract:
The complex pathology of cancer development requires correspondingly complex treatments. The traditional application of individual single-target drugs fails to sufficiently treat cancer with durable therapeutic effects and tolerable adverse events. Therefore, synergistic combinations of drugs represent a promising way to enhance efficacy, overcome toxicity and optimize safety. Chinese Herbal Medicines (CHMs) have long been used as such synergistic combinations. Therefore, we summarized the synergistic combinations of CHMs used in the treatment of cancer and their roles in chemotherapy in terms of enhancing efficacy, reducing side effects, immune modulation, as well as abrogating drug resistance. Our conclusions support the development of further science-based holistic modalities for cancer care.
Keywords:
Cancer treatment, Chinese
medicine, drug resistance, effect, immunity, side effects, synergistic
combination.
Affiliation:
Department of Research Center for
Traditional Chinese Medicine Complexity System, Shanghai University of
Traditional Chinese Medicine, Shanghai, China.
Graphical Abstract:
For More Information Please Visit Our Website Current Cancer Drug Targets
Monday, October 10, 2016
Indian Authors have made substantial contributions to Bentham Science Journal Current Cancer Drug Targets
Journal Name: Current Cancer Drug Targets
Article Title: DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer
Author(s): Varinder Singh, Prince Sharma and Neena Capalash
Abstract
Author(s): Varinder Singh, Prince Sharma and Neena Capalash
Abstract
DNA methylation is an epigenetic modification involved in gene expression regulation. In cancer, the DNA methylation pattern becomes aberrant, causing an array of tumor suppressor genes to undergo promoter hypermethylation and become transcriptionally silent. Reexpression of methylation silenced tumor suppressor genes by inhibiting the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) has emerged as an effective strategy against cancer. The expression of DNA methyltransferase 1 (DNMT1) being high in S-phase of cell cycle makes it a specific target for methylation inhibition in rapidly dividing cells as in cancer. This review discusses nucleoside analogues (azacytidine, decitabine, zebularine, SGI-110, CP-4200), non-nucleoside ihibitors both synthetic (hydralazine, RG108, procaine, procainamide, IM25, disulfiram) and natural compounds (curcumin, genistein, EGCG, resveratrol, equol, parthenolide) which act through different mechanisms to inhibit DNMTs. The issues of bioavailability, toxicity, side effects, hypomethylation resistance and combinatorial therapies have also been highlighted.
For more information, visit:http://benthamscience.com/journal/contents.php?journalID=ccdt&issueID=109879
For details on this article, visit:http://benthamscience.com/journal/abstracts.php?journalID=ccdt&articleID=109882
Courtesy by: Bentham Insight
