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Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule
Yun-Hong Huang1, Bo-Yang Shang, Yong-Su Zhen
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing 100050, China.
Aim:
To study the in vitro and in vivo antitumor effect of lidamycin (LDM) on hepatoma and the active moiety of its molecule.
Methods:
MTT assay was used to determine the growth inhibition of human hepatoma BEL-7402 cells, SMMC-7721 cells and mouse hepatoma H22 cells. The in vivo therapeutic effects of lidamycin and mitomycin C were determined by transplantable hepatoma 22 (H22) in mice and human hepatoma BEL-7402 xenografts in athymic mice.
Results:
In terms of IC(50) values, the cytotoxicity of LDM was 10 000-fold more potent than that of mitomycin C (MMC) and adriamycin (ADM) in human hepatoma BEL-7402 cells and SMMC-7721 cells. LDM molecule consists of two moieties, an aproprotein (LDP) and an enediyne chromophore (LDC). In terms of IC(50) values, the potency of LDC was similar to LDM. However, LDP was 10(5)-fold less potent than LDM and LDC to hepatoma cells. For mouse hepatoma H22 cells, the IC(50) value of LDM was 0.025 nmol/L. Given by single intravenous injection at doses of 0.1, 0.05 and 0.025 mg/kg, LDM markedly suppressed the growth of hepatoma 22 in mice by 84.7%, 71.6% and 61.8%, respectively. The therapeutic indexes (TI) of LDM and MMC were 15 and 2.5, respectively. By 2 iv. injections in two experiments, the growth inhibition rates by LDM at doses of 0.1, 0.05, 0.025, 0.00625 and 0.0125 mg/kg were 88.8-89.5%, 81.1-82.5%, 71.2-74.9%, 52.3-59.575%, and 33.3-48.3%, respectively. In comparison, MMC at doses of 5, 2.5, and 1.25 mg/kg inhibited tumor growth by 69.7-73.6%, 54.0-56.5%, and 31.5-52.2%, respectively. Moreover, in human hepatoma BEL-7402 xenografts, the growth inhibition rates by LDM at doses of 0.05 mg/kg X2 and 0.025 mg/kg X2 were 68.7% and 27.2%, respectively. However, MMC at the dose of 1.25 mg/kg X2 showed an inhibition rate of 34.5%. The inhibition rate of tumor growth by LDM was higher than that by MMC at the tolerated dose.
Conclusion:
Both LDM and its chromophore LDC display extremely potent cytotoxicity to hepatoma cells. LDM shows a remarkable therapeutic efficacy against murine and human hepatomas in vivo.
Insights
Lidamycin (LDM) demonstrates potent antitumor effects against hepatoma cells, significantly inhibiting tumor growth in vivo. Its active component, the enediyne chromophore (LDC), is responsible for this remarkable efficacy.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Biochemistry
Background:
- Hepatocellular carcinoma remains a significant global health challenge, necessitating the development of novel and effective therapeutic agents.
- Lidamycin (LDM) is an antitumor antibiotic with a complex molecular structure, including an enediyne chromophore (LDC) and an apoprotein (LDP).
Purpose of the Study:
- To evaluate the in vitro and in vivo antitumor activity of lidamycin (LDM) against various hepatoma models.
- To identify the active moiety within the LDM molecule responsible for its cytotoxic and therapeutic effects.
Main Methods:
- In vitro cytotoxicity was assessed using the MTT assay on human hepatoma cell lines (BEL-7402, SMMC-7721) and a mouse hepatoma cell line (H22).
- In vivo efficacy was determined using a transplantable mouse hepatoma 22 (H22) model and human hepatoma BEL-7402 xenografts in athymic mice.
- Comparative studies were conducted against mitomycin C (MMC) and adriamycin (ADM) to establish relative potency and therapeutic index.
Main Results:
- LDM exhibited significantly higher cytotoxicity than MMC and ADM against human hepatoma cells, with IC50 values 10,000-fold lower.
- The enediyne chromophore (LDC) was identified as the primary active moiety, showing potency comparable to LDM, while the apoprotein (LDP) was largely inactive.
- In vivo studies demonstrated substantial tumor growth inhibition by LDM in both murine (H22) and human (BEL-7402 xenografts) models, outperforming MMC at tolerated doses with a higher therapeutic index.
Conclusions:
- LDM and its active chromophore LDC possess exceptionally potent cytotoxic activity against hepatoma cells.
- LDM demonstrates significant therapeutic efficacy in preclinical models of both murine and human hepatoma, highlighting its potential as an anticancer agent.
