Selective apoptotic killing of solid and hematologic tumor cells by bombesin-targeted delivery of mitochondria-disrupting peptides.
Tumor-homing peptides are attractive tools for tumor imaging and targeted therapy due to their ability to specifically bind and enter tumor cells and masses. Bombesin and its analogues show promise for the targeted delivery of radioactive and chemotherapeutic agents to a wide variety of solid tumors. Here, we describe the bombesin-targeted delivery of toxic peptides to solid tumor cells and leukemia cells. We found that bombesin specifically bound to solid tumor cells and leukemia cells with similar affinity. Conjugation to bombesin significantly (5-15 times) enhanced the cytotoxicity of three mitochondria-disrupting peptides (KLA, B27, and B28) in solid tumor cells and leukemia cells through improvement of their binding affinity. The bombesin-directed peptides (KB, BB27, and BB28) contained the same bombesin leader sequence but had different mitochondria-disrupting peptides, which selectively induced caspase-dependent apoptosis in solid tumor cells and leukemia cell lines. The IC50 values of these peptides (BB27, 3-5 micromol/L; BB28, 4-6 micromol/L) for solid tumor cells and leukemia cells are approximately 5-10 times lower than the IC50 values for normal cells. BB27 and BB28 also displayed cytotoxicity in primary leukemia cells from patients (n = 4) with acute myeloid leukemia. Intratumoral (10 mg/kg) and intraperitoneal (20 mg/kg) injection of BB27 and BB28 exerted substantial inhibition on K562 tumor xenograft growth without obvious systematic toxicity. Our results suggest that the bombesin-directed mitochondria-disrupting peptides BB27 and BB28 might be used as therapeutic agents not only for solid tumors but also for hematologic tumors.
Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, and Department of Hematology, West China Hospital, Sichuan University, Chengdu, 610041 China.
Huawei
H
Cai
Hao
H
Yang
Bin
B
Xiang
Shengfu
S
Li
Shan
S
Liu
Lin
L
Wan
Jie
J
Zhang
Youping
Y
Li
Jingqiu
J
Cheng
Xiaofeng
X
Lu
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001839:Bombesin / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010455:Peptides; D001839:Bombesin