Detail of "34408-14-5"

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RNA-Directed Actions of 8-Chloro-Adenosine in Multiple Myeloma Cells

RNA-Directed Actions of 8-Chloro-Adenosine in Multiple Myeloma Cells. Stellrecht, Christine M.; Rodriguez, Carlos O., Jr.; Ayres, Mary; Gandhi, Varsha (Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA). Cancer Research, 63(22), 7968-7974 (English) 2003 American Association for Cancer Research. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The purine analog, 8-chloro-adenosine (8-Cl-Ado), induces apoptosis in a no. of multiple myeloma (MM) cell lines. This ribonucleoside analog accumulates as a triphosphate and selectively inhibits RNA synthesis without perturbing DNA synthesis. Cellular RNA is synthesized by one of three polymerases (Pol I, II, or III); thus, the inhibition of one or more RNA polymerases may be mediating 8-Cl-Ado cytotoxicity. Here, we have addressed this question by dissecting the RNA-directed actions of 8-Cl-Ado in MM cells. Differential alterations in [3H]uridine incorporation were found in the three major classes of RNA after a 20-h exposure with 10 mM 8-Cl-Ado. The synthesis rate of Pol III transcripts, 5 S and tRNA, remained unchanged, whereas Pol I-mediated rRNA synthesis decreased by ~20%. In contrast, mRNA synthesis, which is transcribed by Pol II, rapidly declined within 4 h and reached a 50% decrease, which was maintained for 20 h. Parallel to RNA synthesis inhibition, 8-Cl-Ado was maximally incorporated in the mRNA (>13 nmol/mg RNA), which was 5-fold higher than the tRNA and rRNA incorporation. Electrophoretic and radiog. anal. of newly synthesized and processed [14C]uridine-labeled transcripts indicated that the analog blocks transcription elongation. 9014-24-8 and 34408-14-5 which are cas registry numbers of substances are two of reagents here. Consistent with that result, high-performance liq. chromatog. anal. of micrococcal nuclease and spleen phosphodiesterase-digested RNA demonstrated that the analog incorporation is at the 3' terminus. In conclusion, our data demonstrate that in MM cells, 8-Cl-Ado is preferentially incorporated into mRNA, suggesting a propensity toward Pol II, and inhibits RNA synthesis by premature transcriptional chain termination. .

Anti-proliferative effects of 8-chloro-cAMP and other cAMP analogs are unrelated to their effects on protein kinase A regulatory subunit expression

Anti-proliferative effects of 8-chloro-cAMP and other cAMP analogs are unrelated to their effects on protein kinase A regulatory subunit expression. Lamb, Darija; Steinberg, Robert A. (Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA). Journal of Cellular Physiology, 192(2), 216-224 (English) 2002 Wiley-Liss, Inc. CODEN: JCLLAX. ISSN: 0021-9541. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Conflicting reports have attributed 8-chloro-cAMP (Cl-cAMP)-mediated inhibition of tumor cell growth to either a toxic 8-chloro-adenosine (Cl-AdR) breakdown product or a Cl-cAMP-mediated decrease in ratio of Type I to Type II regulatory (R) subunits of protein kinase A (PKA). Using the MCF-7 human breast cancer and S49 mouse lymphoma cell lines as models, we show that the effects of Cl-cAMP and other cAMP analogs on growth and R subunit expression are unrelated. MCF-7 cell growth was insensitive to most analogs and inducers of cAMP, but was potently inhibited by Cl-cAMP acting through uptake and phosphorylation of its Cl-AdR breakdown product. Possible roles of adenosine receptors or P2 purinoceptors in these Cl-cAMP-mediated growth effects were ruled out by studies with agonists and antagonists. Cholera toxin markedly decreased the ratio of Type I to Type II R subunits in MCF-7 cells without affecting growth, while growth inhibitory concns. of Cl-cAMP or Cl-AdR had insignificant effects on this ratio. In S49 cells, where PKA activation is known to inhibit cell growth, PKA-deficient mutants retained sensitivity to both Cl-cAMP and the related 8-bromo-cAMP. 34408-14-5 and 41941-56-4 are also in the experiment. Adenosine kinase (AK)-deficient S49 cells were inhibited only by higher concns. of these 8-halogenated cAMP analogs. Of the commonly used cAMP analogs, only 8-(4-chlorophenylthio)-cAMP acted purely as a cyclic nucleotide-having no effect on PKA-deficient cells, but strongly inhibiting both wild-type and AK-deficient cells. Where growth inhibitory concns. of most cAMP analogs reduced RI expression in the AK-deficient mutant, a functionally equiv. concn. of (N6, O2')dibutyryl-cAMP maintained or increased this expression. .