[Synergistic Inhibitory Effect of Arsenic Trioxide Combined with Itraconazole on Hedgehog Pathway of Multiple Myeloma
Xiao-Bing Huang1, Yi Shi2, Chun-Sheng Wang1
1Department of Hematology, Sichuan People's Hospital of Sichuan Academy of Medical Sciences, Chengdu 610072, Sichuan Province, China.
Objective:
To investigate the antitumor effect of arsenic trioxide (ATO) combined with itraconazole (ITRA) on human multiple myeloma NCI-H929 cells by synergistically inhibiting Hedgehog (HH) signaling pathway.
Methods:
The inhibitory rate of NCI-H929 cells was assayed by MTT method. Tumor weight, tumor weight inhibition rate, and tumor volume of mouse model with multiple myeloma were examined. The ELISA were appled to detect the M-protein, qPCR and Western blot were used respectively to detect the expression level of Ptch, SMO, Gli and downstream target genes, the survival rate of tumor-bearing mice was analyzed.
Results:
ATO combined with ITRA significantly inhibited NCI-H929 cell proliferation as compared with a single administration. The combination of ATO and ITRA could synergistically inhibit tumor growth and obviously reduced tumor burden, survival time of tumor-bearing mice was significantly prolonged. qPCR and Western blot results confirmed that the ATO combined with ITRA could significantly down-regulated expression of Gli1, leading to significantly decrease of cyclinD1 and BCL-2 expression levels.
Conclusion:
ATO combined with ITRA can more strongly suppress the growth of multiple myeloma NCI-H929 cells, as compared with a single administration. The synergistic effect of ATO and ITRA significantly down-regulates expression of Gli1 in HH signaling pathway, moreover the inhibition of target gene overexpression may be one of two drug mechanisms.
Insights
Arsenic trioxide (ATO) and itraconazole (ITRA) synergistically inhibit multiple myeloma growth by targeting the Hedgehog signaling pathway. This combination therapy significantly reduces tumor burden and prolongs survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells.
- The Hedgehog (HH) signaling pathway plays a crucial role in the pathogenesis and progression of various cancers, including multiple myeloma.
- Targeting the HH pathway presents a potential therapeutic strategy for multiple myeloma.
Purpose of the Study:
- To evaluate the combined antitumor effect of arsenic trioxide (ATO) and itraconazole (ITRA) on human multiple myeloma NCI-H929 cells.
- To investigate the synergistic inhibition of the Hedgehog (HH) signaling pathway by ATO and ITRA.
- To assess the impact of this combination therapy on tumor growth and survival in a preclinical multiple myeloma model.
Main Methods:
- Cell proliferation was assessed using the MTT assay.
- Tumor growth, weight, and volume were measured in a mouse model of multiple myeloma.
- Expression levels of HH pathway components (Ptch, SMO, Gli1) and downstream targets (cyclinD1, BCL-2) were analyzed by qPCR and Western blot.
- M-protein levels were detected using ELISA, and survival rates of tumor-bearing mice were analyzed.
Main Results:
- The combination of ATO and ITRA demonstrated significantly enhanced inhibition of NCI-H929 cell proliferation compared to single agents.
- Combined ATO and ITRA treatment synergistically suppressed tumor growth, reduced tumor burden, and significantly prolonged the survival time of tumor-bearing mice.
- qPCR and Western blot analyses confirmed that ATO and ITRA significantly downregulated Gli1 expression, leading to decreased expression of cyclinD1 and BCL-2.
Conclusions:
- ATO combined with ITRA exhibits a potent synergistic effect in suppressing the growth of multiple myeloma NCI-H929 cells.
- The synergistic antitumor effect is mediated, at least in part, by the significant downregulation of Gli1 within the HH signaling pathway.
- Inhibition of target gene overexpression, such as cyclinD1 and BCL-2, represents a key mechanism underlying the dual-drug action.
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