Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and suberoylanilide hydroxamic acid in lymphoma cell lines.
Hematopoietic stem cell transplant (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in acute myeloid leukemia (AML). We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs - clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) - resulted in synergistic cytotoxicity in lymphoma cell lines. We demonstrated that the [2 NAs + Bu] combination activates a DNA damage response through the ATM-CHK2 and ATM-CHK1 pathways, leading to cell cycle checkpoint activation and apoptosis. Histone modifications and KAP1 phosphorylation are indicative of chromatin relaxation mediated by the nucleoside analogs, which sequentially increase Bu alkylation. Addition of suberoylanilide hydroxamic acid (SAHA) enhanced chromatin relaxation through increased histone acetylation and further augmented the cytotoxicity of [2 NAs + Bu]. Our results provide a preclinical basis for a clinical trial on using [2 NAs + Bu ± SAHA] combinations as conditioning therapy for patients with chemotherapy-refractory lymphoma undergoing HSCT.
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX , USA. bvaldez@mdanderson.org
Benigno C
BC
Valdez
David
D
Murray
Yago
Y
Nieto
Yang
Y
Li
Guiyun
G
Wang
Richard E
RE
Champlin
Borje S
BS
Andersson
D000107:Acetylation; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002066:Busulfan / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D006657:Histones; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D009705:Nucleosides / Q000494:pharmacology; D019172:Transplantation Conditioning / Q000379:methods; D000077337:Vorinostat
D018906:Antineoplastic Agents, Alkylating; D006657:Histones; D006877:Hydroxamic Acids; D009705:Nucleosides; D000077337:Vorinostat; D002066:Busulfan