title: Intracellular succinylation of 8-chloroadenosine and its effect on fumarate levels.
abstract: 8-Chloroadenosine (8-Cl-Ado) is a ribosyl nucleoside analog currently in phase I testing for the treatment of chronic lymphocytic leukemia (CLL). 8-Cl-Ado activity is dependent on adenosine kinase and requires intracellular accumulation of 8-Cl-Ado as mono-, di-, and tri-phosphates. In the current study with four mantle cell lymphoma cell lines, we report a new major metabolic pathway for 8-Cl-Ado intracellular metabolism, the formation of succinyl-8-chloro-adenosine (S-8-Cl-Ado) and its monophosphate (S-8-Cl-AMP). 8-Cl-AMP levels were highly associated with S-8-Cl-AMP levels and reached a steady-state prior to the secondary metabolites, 8-Cl-ATP and S-8-Cl-Ado. Consistent with fumarate as a required substrate for formation of succinyl-8-Cl-adenylate metabolites, the S-8-Cl-adenylate concentrations in multiple cell lines were associated with fumarate loss. The distribution of metabolites was also altered using the energy metabolism modifiers, metformin and oligomycin. The rates of succinyl-8-Cl-adenylate metabolism were enhanced by increasing the intracellular fumarate concentrations after metformin co-treatment. In addition, the S-8-Cl-AMP concentrations were increased after acute inhibition of ATP synthase by oligomycin. We conclude that 8-Cl-Ado metabolism not only affects intracellular purine metabolism; 8-Cl-Ado conversion to succinyl analogs ties its metabolism to the citric acid cycle by reduction of the fumarate pool.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dennison
authors.forename: Mary L
authors.initials: ML
authors.lastname: Ayres
authors.forename: Kumar
authors.initials: K
authors.lastname: Kaluarachchi
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D011687:Purines / Q000378:metabolism; D019802:Succinic Acid / Q000737:chemistry / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005650:Fumarates; D007004:Hypoglycemic Agents; D009840:Oligomycins; D011687:Purines; D014475:Uncoupling Agents; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D008687:Metformin; D019802:Succinic Acid; C044258:8-chloro-cyclic adenosine monophosphate; C075440:8-chloroadenosine