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Synergistic effects of geldanamycin and antitumor drugs
Z Y Liao1, S H Zhang, Y S Zhen
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Aim:
To study the effect of geldanamycin (GDM) on cell-cycle of human hepatoma BEL-7402 cells and the antitumor activity of cisplatin and mitomycin C in combination with GDM in vitro and in vivo.
Methods:
MTT assay was used to determine the growth inhibition of hepatoma BEL-7402 cells. Cell cycle was analyzed by flow cytometry. Transplantable murine hepatoma 22 model was used to evaluate the antitumor activity of drugs in vivo.
Results:
The IC50 value of GDM for hepatoma BEL-7402 cells by MTT assay was found to be 0.28 mumol.L-1. At concentrations of 0.1, 1.0, and 10 mumol.L-1, GDM reduced the proportion of S phase and induced G2/M arrest in BEL-7402 cells. At relatively low cytotoxic concentration, 0.1 or 0.2 mumol.L-1, GDM markedly potentiated the cytotoxicity of a series of chemotherapeutic agents including cisplatin, mitomycin C, adriamycin and cytarabine against BEL-7402 cells. The inhibition of tumor growth by cisplatin and mitomycin C was also enhanced in transplantable hepatoma 22-bearing mice when these agents were administered in combination with GDM 0.38 mg.kg-1. The synergistic effects were very significant with CDI < 0.7.
Conclusion:
These results suggest that GDM, as a biochemical modulator targeting Hsp90 function, may be potentially useful in cancer chemotherapy.
Insights
Geldanamycin (GDM) halts cancer cell division and enhances chemotherapy effectiveness against liver tumors. This study shows GDM combined with cisplatin or mitomycin C significantly boosts antitumor activity in vitro and in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) remains a significant global health challenge.
- Targeting heat shock protein 90 (Hsp90) is a promising strategy in cancer therapy.
- Geldanamycin (GDM) is an Hsp90 inhibitor with potential anticancer properties.
Purpose of the Study:
- To investigate the impact of Geldanamycin (GDM) on the cell cycle of human hepatoma BEL-7402 cells.
- To evaluate the in vitro and in vivo antitumor efficacy of combining GDM with cisplatin and mitomycin C.
Main Methods:
- Cell growth inhibition was assessed using MTT assays.
- Cell cycle distribution was analyzed via flow cytometry.
- Antitumor activity was evaluated in a murine hepatoma 22 transplantable tumor model.
Main Results:
- GDM demonstrated a significant IC50 of 0.28 μmol/L against BEL-7402 cells.
- GDM induced G2/M phase arrest in BEL-7402 cells.
- GDM potentiated the cytotoxicity of cisplatin, mitomycin C, adriamycin, and cytarabine, and enhanced tumor growth inhibition in vivo.
Conclusions:
- Geldanamycin (GDM), by modulating Hsp90 function, shows potential as a valuable adjunct in cancer chemotherapy.
- Combination therapy with GDM may offer enhanced therapeutic benefits for liver cancer treatment.