title: CDA-2, a urinary preparation, inhibits lung cancer development through the suppression of NF-kappaB activation in myeloid cell.
abstract: CDA-2 (cell differentiation agent 2), a urinary preparation, has potent anti- proliferative and pro-apoptotic properties in cancer cells. However, the mechanisms of tumor inhibitory action of CDA-2 are far from clear, and especially there was no report on lung cancer. Here we demonstrate that CDA-2 and its main component phenylacetylglutamine (PG) reduce the metastatic lung tumor growth, and increases survival time after inoculation with Lewis lung carcinoma (LLC) cells in a dose-dependent manner in C57BL6 mice. Proliferative program analysis in cancer cells revealed a fundamental impact of CDA-2 and PG on proliferation and apoptosis, including Bcl-2, Bcl-XL, cIAP1, Survivin, PCNA, Ki-67 proteins and TUNEL assays. CDA-2 and PG significantly reduced NF-κB DNA-binding activity in lung cancer cells and in alveolar macrophages of tumor bearing mice and especially decreased the release of inflammatory factors including TNFα, IL-6, and KC. Furthermore, CDA-2 and PG decrease the expressions of TLR2, TLR6, and CD14, but not TLR1, TLR3, TLR4, and TLR9 in bone-marrow-derived macrophages (BMDM) of mice stimulated by LLC-conditioned medium (LLC-CM). Over-expressing TLR2 in BMDM prevented CDA-2 and PG from inhibiting NF-κB activation, as well as induction of TNFα and IL-6. TLR2:TLR6 complexes mediate the effect of NF-κB inactivation by CDA-2. In conclusion, CDA-2 potently inhibits lung tumor development by reduction of the inflammation in lung through suppression of NF-κB activation in myeloid cells, associating with modulation of TLR2 signaling.
authors.affiliation: Department of Pharmacy, Putuo People's Hospital, Shanghai, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Cui-Min
authors.initials: CM
authors.lastname: Jiang
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Wan
authors.forename: Jun-Lu
authors.initials: JL
authors.lastname: Wu
authors.forename: Wen-Qiang
authors.initials: WQ
authors.lastname: Quan
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
authors.forename: Kai-Yin
authors.initials: KY
authors.lastname: Wu
authors.forename: Dong
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase