Chlorambucil-conjugated platinum(IV) prodrugs to treat triple-negative breast cancer in vitro and in vivo.
Modification of platinum (II) into lipophilic platinum (IV) compounds by introducing biologically active molecules were widely employed to develop new platinum-based prodrugs in the past decade. In this paper, two chlorambucil platinum (IV) complexes, CLB-Pt and CLB-Pt-CLB, were synthesized and displayed very potent antiproliferative activity against all the tested cancer cell lines, such as A549, HeLa and MCF-7, especially to treat the well-known refractory triple-negative breast cancer. CLB-Pt-CLB significantly improved cell-killing effect in triple-negative subtype MDA-MB-231 cells, and showed much stronger cytotoxicity than either monotherapy or combination of cisplatin and chlorambucil. CLB-Pt-CLB prodrug entered cells in dramatically increased amount compared with cisplatin and enhanced DNA damage, inducing cancer cell apoptosis. It exhibited high anticancer activity and no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. The chlorambucil moiety not only greatly assisted the passive diffusion of CLB-Pt-CLB into cells, but also produced the synergism with cisplatin in targeting DNA.
['Ma|Zhong-Ying|ZY|', 'Wang|Dong-Bo|DB|', 'Song|Xue-Qing|XQ|', 'Wu|Yi-Gang|YG|', 'Chen|Qian|Q|', 'Zhao|Chun-Lai|CL|', 'Li|Jing-Yi|JY|', 'Cheng|Shi-Hao|SH|', 'Xu|Jing-Yuan|JY|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D049109:Cell Proliferation D002699:Chlorambucil D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D005260:Female D006801:Humans D051379:Mice D008819:Mice, Nude D015394:Molecular Structure D009944:Organoplatinum Compounds D011355:Prodrugs D013329:Structure-Activity Relationship D064726:Triple Negative Breast Neoplasms D014945:Wound Healing
Platinum(IV) prodrugs Triple-negative breast cancer Chlorambucil Cisplatin Decreased toxicity Synergistic effects