Selective apoptotic killing of solid and hematologic tumor cells by bombesin-targeted delivery of
Huawei Cai1, Hao Yang, Bin Xiang
1Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, and Department of Hematology, West China Hospital, Sichuan University, Chengdu, 610041 China.
Abstract:
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.
Insights
Bombesin-targeted toxic peptides show enhanced cancer cell killing. These novel peptides, BB27 and BB28, effectively target solid tumors and leukemia cells, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- Tumor-homing peptides facilitate targeted delivery of therapeutics.
- Bombesin analogues are effective for targeting various solid tumors.
Purpose of the Study:
- To investigate bombesin-targeted delivery of toxic peptides to solid tumor and leukemia cells.
- To evaluate the efficacy and safety of bombesin-conjugated peptides for cancer therapy.
Main Methods:
- Conjugation of bombesin to mitochondria-disrupting peptides (KLA, B27, B28) to create BB27 and BB28.
- Assessment of binding affinity, cytotoxicity, and apoptosis induction in cancer cell lines and primary leukemia cells.
- Evaluation of in vivo efficacy and toxicity in tumor xenograft models.
Main Results:
- Bombesin demonstrated specific binding to solid tumor and leukemia cells.
- Bombesin conjugation significantly enhanced peptide cytotoxicity (5-15 fold) by improving binding affinity.
- BB27 and BB28 selectively induced apoptosis in cancer cells with lower IC50 values compared to normal cells.
- BB27 and BB28 showed cytotoxicity in primary acute myeloid leukemia cells and inhibited tumor xenograft growth without systemic toxicity.
Conclusions:
- Bombesin-directed mitochondria-disrupting peptides (BB27, BB28) are effective against solid tumors and hematologic malignancies.
- These peptides offer a potential therapeutic strategy for both solid and blood cancers.
- The targeted approach minimizes toxicity, suggesting clinical applicability.
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