Anthracyclines React with Apurinic/Apyrimidinic Sites in DNA

被引：6

作者：

Bellamri, Medjda ^{[1
,2
]}

Terrell, John T. ^{[3
]}

Brandt, Kyle ^{[1
,2
]}

Gruppi, Francesca ^{[3
]}

Turesky, Robert J. ^{[1
,2
]}

Rizzo, Carmelo J. ^{[4
,5
]}

机构：

[1] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA

[3] Vanderbilt Univ, Chem, Nashville, TN 37235 USA

[4] Vanderbilt Univ, Chem, Biochem, Nashville, TN 37235 USA

[5] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA

来源：

ACS CHEMICAL BIOLOGY | 2023年 / 18卷 / 06期

关键词：

BASE EXCISION-REPAIR; ABASIC SITES; CROSS-LINKS; FACILE FORMATION; ADDUCT FORMATION; FORMALDEHYDE; MUSTARD; DRUG; SEMICARBAZIDE; QUANTITATION;

D O I：

10.1021/acschembio.3c00033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The combination of doxorubicin (Adriamycin) and cyclophosphamide,referred to as AC chemotherapy, is commonly used for the clinicaltreatment of breast and other cancers. Both agents target DNA withcyclophosphamide causing alkylation damage and doxorubicin stabilizingthe topoisomerase II-DNA complex. We hypothesize a new mechanismof action whereby both agents work in concert. DNA alkylating agents,such as nitrogen mustards, increase the number of apurinic/apyrimidinic(AP) sites through deglycosylation of labile alkylated bases. Herein,we demonstrate that anthracyclines with aldehyde-reactive primaryand secondary amines form covalent Schiff base adducts with AP sitesin a 12-mer DNA duplex, calf thymus DNA, and MDA-MB-231 human breastcancer cells treated with nor-nitrogen mustard and the anthracyclinemitoxantrone. The anthracycline-AP site conjugates are characterizedand quantified by mass spectrometry after NaB-(CN)-H-3 orNaBH(4) reduction of the Schiff base. If stable, the anthracycline-APsite conjugates represent bulky adducts that may block DNA replicationand contribute to the cytotoxic mechanism of therapies involving combinationsof anthracyclines and DNA alkylating agents.

引用

页码：1315 / 1323

页数：9

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