Cancer pharmacogenetics: polymorphisms, pathways and beyond (original) (raw)
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Moonlighting Adenosine Deaminase: A Target Protein for Drug Development
Medicinal Research Reviews, 2014
Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest.
Journal of the National Cancer Institute
Background: Although single nucleotide polymorphisms may be potentially important pharmacogenetic determinants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used chemotherapeutic agents for colon and breast cancers, because the modes of action of 5FU and MTX are critically dependent on cellular composition of folates. Methods: Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with wild-type or mutant 677T human MTHFR cDNA. MTHFR enzyme activity and thermolability, intracellular folate composition, growth rate, and catalytic thymidylate synthase activity were determined. In vitro chemosensitivity to 5FU and MTX was determined using the sulforhodamine B assay. In vivo chemosensitivity of HCT116 cells to 5FU was determined in nude mice. Results: Compared with cells expressing the wildtype MTHFR, HCT116 and MDA-MB-435 cells expressing the mutant 677T MTHFR had decreased MTHFR activity, MTHFR thermolability, changed intracellular folate distribution, accelerated cellular growth rate, and increased thymidylate synthase activity. The MTHFR 677T mutation increased chemosensitivity of colon and breast cancers to 5FU, but decreased chemosensitivity of breast cancer cells to MTX. In nude mice, xenografts expressing the mutant 677T MTHFR grew faster, but were more sensitive to 5FU, than xenografts expressing the wild-type protein. Conclusions: Our data provide evidence that the MTHFR C677T polymorphism affects the concentration and intracellular distribution of folates and changes the growth and chemosensitivity of colon and breast cancer cells. The MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy. [J Natl Cancer Inst 2004;96:134 -44]
Molecular Cancer Therapeutics, 2006
Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA ribosideinduced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of com-pounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention. [Mol Cancer Ther 2006;5(9):2211 -7]
JNCI Journal of the National Cancer Institute, 2004
Background: Although single nucleotide polymorphisms may be potentially important pharmacogenetic determinants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used chemotherapeutic agents for colon and breast cancers, because the modes of action of 5FU and MTX are critically dependent on cellular composition of folates. Methods: Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with wild-type or mutant 677T human MTHFR cDNA. MTHFR enzyme activity and thermolability, intracellular folate composition, growth rate, and catalytic thymidylate synthase activity were determined. In vitro chemosensitivity to 5FU and MTX was determined using the sulforhodamine B assay. In vivo chemosensitivity of HCT116 cells to 5FU was determined in nude mice. Results: Compared with cells expressing the wildtype MTHFR, HCT116 and MDA-MB-435 cells expressing the mutant 677T MTHFR had decreased MTHFR activity, MTHFR thermolability, changed intracellular folate distribution, accelerated cellular growth rate, and increased thymidylate synthase activity. The MTHFR 677T mutation increased chemosensitivity of colon and breast cancers to 5FU, but decreased chemosensitivity of breast cancer cells to MTX. In nude mice, xenografts expressing the mutant 677T MTHFR grew faster, but were more sensitive to 5FU, than xenografts expressing the wild-type protein. Conclusions: Our data provide evidence that the MTHFR C677T polymorphism affects the concentration and intracellular distribution of folates and changes the growth and chemosensitivity of colon and breast cancer cells. The MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy. [J Natl Cancer Inst 2004;96:134 -44]
Journal of Biological Chemistry, 2004
Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K i values of 8 and 6 nM, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 Å with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn 431 in the reaction mechanism along with previously identified key catalytic residues Lys 266 and His 267. Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonylcontaining antifolates. Cancer is responsible for 25% of all deaths within the United States, making it one of the leading causes of mortality second only to heart disease (1). As multiple metabolic pathways are implicated in disease initiation and progression, substantial efforts have been focused on inhibition of pathways that would either limit the spread of or completely eradicate tumors. In particular two enzymes, glycinamide ribonucleotide (GAR) 1
Anticancer research, 2013
BACKGROUND/AIM GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219. MATERIALS AND METHODS A cell line resistant to 9-(2-Phosphonylmethoxyethyl)-N(6)-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. RESULTS The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. CONCLUSION The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the d...
Pharmacogenetics of 5-fluorouracil: a new way to trounce the gastric cancer
Gastric cancer cases are significantly increasing worldwide. In fast few years varieties of chemotherapy drug are developed for the treatment of gastric cancer. Among these drugs 5-fluorouracil (5-FU) is broadly in used. Effectiveness of 5-FU get significantly reduced due to single nucleotide polymorphisms (SNP) in drug metabolizing enzymes (DME). Thus due to the SNP, adverse drug reaction are reported in cancer patient. In order to minimize the side effect, personalized medicine has to be developed according to the individual's genotype, where pharmacogenetics can add a boost in chemotherapy regime. The US Food and Drug Administration (FDA) had sanctioned eighty numbers of drugs holding genetic information. In this review, we discuss impact of polymorphisms in four specific drug metabolizing enzyme; Dihydropyrimidine dehydrogenase (DPD),Thymidylate synthase (TYMS),Methylenetetrahydrofolate reductase(MTHFR) and Thymidylate phosphorylase(TP) and their effects on 5-fluorouracil.