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Downregulation of Sp1 by Minnelide leads to decrease in HSP70 and decrease in tumor burden of gastric cancer
Nivedita Arora1, Osama Alsaied1, Patricia Dauer1,2
1Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.
Background:
Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11.
Methods:
Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice.
Results:
Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model.
Conclusion:
Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers.
Insights
Triptolide and its pro-drug Minnelide show promise in treating gastric cancer by reducing cell viability and tumor growth. Combining Minnelide with CPT-11 significantly shrinks tumors, offering hope for new gastrointestinal cancer therapies.
Area of Science:
- Oncology
- Pharmacology
Background:
- Gastric cancer is a leading cause of cancer mortality with poor survival rates.
- Existing chemotherapies show limited efficacy against stomach cancer.
- Triptolide and its pro-drug Minnelide were investigated for their anti-cancer effects.
Purpose of the Study:
- To evaluate the efficacy of triptolide and Minnelide as monotherapy and in combination with CPT-11 against gastric adenocarcinoma.
- To assess the impact of these agents on gastric cancer cell viability, apoptosis, and tumor growth in preclinical models.
Main Methods:
- In vitro treatment of gastric cancer cell lines (MKN28, MKN45) with triptolide.
- Assessment of cell viability using MTT assay and apoptosis via caspase activity.
- In vivo evaluation of Minnelide in athymic nude mice xenograft models, including combination therapy with CPT-11.
Main Results:
- Triptolide treatment decreased cell viability and increased apoptosis in gastric cancer cell lines.
- Minnelide administration reduced tumor burden in both MKN28 and MKN45 xenograft models.
- Combination therapy of Minnelide and CPT-11 demonstrated significant tumor reduction in the NCI-N87 model.
Conclusions:
- Minnelide, particularly in combination with CPT-11, shows significant potential for gastric cancer treatment.
- These findings support the ongoing clinical trials of Minnelide for gastrointestinal cancers.
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