title: ALDH1A1 mediates resistance of diffuse large B cell lymphoma to the CHOP regimen.
abstract: Although there have been substantial advances in our knowledge of the resistance of diffuse large B cell lymphoma (DLBCL) to chemotherapy, there are few efficient treatment strategies for recurrent/refractory DLBCL. The aim of this study was to investigate the role of aldehyde dehydrogenase (ALDH) 1A1 in the resistance of diffuse large B cell lymphoma to the chemotherapeutic mixture consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The involvement of ALDH1A1 in DLBCL was elucidated by knockdown and pharmacologic inhibition; Cell Counting Kit-8 (CCK-8) and clone formation assays were used to determine its role in CHOP sensitivity and clone formation ability. Caspase colorimetric assay was used to measure the extent of apoptosis. Western blot analysis was used to measure signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF-κB) signaling proteins, and quantitative real-time PCR (RT-PCR) was used to measure the differential expression of ALDH1A1 of DLBCL patients and healthy donors. ALDH1A1 showed a 5.64-fold higher expression in malignant B cells than in normal B cells. Diethylaminobenzaldehyde (DEAB) decreased the half maximal inhibitory concentration (IC50) of the CHOP regimen in Farage cells from 344.78 ± 65.75 to 183.88 ± 49.75 ng/ml (P = 0.004). Both knockdown and inhibition of ALDH1A1 reduced clonogenicity, increased caspase-3/caspase-9 activity, and attenuated the phosphorylation status of STAT3/NF-κB. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels of expression (P = 0.044). ALDH1A1 is a new mediator for resistance of DLBCL to CHOP; it is a predictor of clinical prognosis and may serve as a potential target to improve chemotherapy responsiveness of human DLBCL.
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, 88 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Song
authors.forename: Mei-Zuo
authors.initials: MZ
authors.lastname: Zhong
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Gan
authors.forename: Ping-Yong
authors.initials: PY
authors.lastname: Yi
authors.forename: You-Hong
authors.initials: YH
authors.lastname: Tang
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Liu
authors.forename: Jin-Qiong
authors.initials: JQ
authors.lastname: Jiang
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D034622:RNA Interference; D050697:Retinal Dehydrogenase; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D053148:Caspase 3; D053453:Caspase 9; D011241:Prednisone