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The GSTP1/MAPKs/BIM/SMAC modulatory actions of nitazoxanide: Bioinformatics and experimental evidence in subcutaneous
Samar Imbaby1, Shereen E Elkholy2, Salwa Faisal3
1Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
Aims:
Ehrlich ascites carcinoma and its subcutaneous inoculated solid tumour form (SEC) are reliable models for chemotherapeutic molecular targets exploration. Novel chemotherapeutic approaches are identified as molecular targets for intrinsic apoptosis, like the modulation of the second mitochondria-derived activator of caspases (SMAC). SMAC is a physiological substrate of mitogen-activated protein kinases (MAPKs). Glutathione-S-transferase P1 (GSTP1) and its close association with MAPKs play an important role in malignant cell proliferation, metastasis, and resistance to chemotherapeutics. Nitazoxanide (NTZ) is an emerging cancer therapy and its targeted GSTP1 evidence remains a knowledge need.
Main Methods:
In the present mice-established SEC, the chemotherapeutic roles of oral NTZ (200 mg/kg/day) and 5-fluorouracil (5-FU; 20 mg/kg/day, intraperitoneally) regimens were evaluated by measuring changes in tumour mass, the tumour MAPKs, cytochrome c, Bcl-2 interacting mediator of cell death (BIM), and SMAC signalling pathway in addition to its molecular downstream; caspases 3 and 9.
Key Findings:
Computational analysis for these target protein interactions showed direct-ordered interactions. After individual therapy with NTZ and 5-FU regimens, the histological architecture of the extracted tumour discs revealed decreases in viable tumour regions with significant necrosis surrounds. These findings were consistent with gross tumour sizes. Each separate regimen lowered the remarkable GSTP1 and elevated the low MAPKs expressions, cytochrome c, BIM, SMAC, and caspases 3, and 9 in EST tissues.
Significance:
The chemotherapeutic activity of NTZ in SEC was proven. Additionally, NTZ possesses a SMAC modulatory activity that, following thorough research, should be taken into consideration as a chemotherapeutic approach in solid tumours.
Insights
Nitazoxanide (NTZ) shows chemotherapeutic activity against solid tumors by modulating the SMAC pathway. This study demonstrates NTZ
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ehrlich ascites carcinoma (SEC) models are crucial for exploring novel chemotherapeutic targets.
- The second mitochondria-derived activator of caspases (SMAC) pathway is a key target for intrinsic apoptosis.
- Glutathione-S-transferase P1 (GSTP1) and mitogen-activated protein kinases (MAPKs) are implicated in cancer progression and drug resistance.
Purpose of the Study:
- To evaluate the chemotherapeutic efficacy of Nitazoxanide (NTZ) in a solid Ehrlich ascites carcinoma (SEC) model.
- To investigate NTZ's impact on the SMAC signaling pathway, including MAPKs, GSTP1, and downstream caspases.
- To compare NTZ's effects with 5-fluorouracil (5-FU), a standard chemotherapeutic agent.
Main Methods:
- Mice bearing subcutaneous Ehrlich ascites carcinoma (SEC) were treated with oral NTZ (200 mg/kg/day) or intraperitoneal 5-FU (20 mg/kg/day).
- Tumor mass, MAPKs, cytochrome c, BIM, SMAC, caspases 3, and 9 levels were measured.
- Computational analysis was performed to understand target protein interactions.
Main Results:
- Both NTZ and 5-FU treatments significantly reduced tumor size and induced necrosis.
- NTZ and 5-FU decreased GSTP1 expression and increased MAPKs expression in tumor tissues.
- Both regimens elevated levels of cytochrome c, BIM, SMAC, caspases 3, and 9, indicating apoptosis induction.
Conclusions:
- Nitazoxanide (NTZ) demonstrates significant chemotherapeutic activity in a solid tumor model.
- NTZ effectively modulates the SMAC pathway, suggesting its potential as a novel therapeutic strategy for solid tumors.
- Further research into NTZ's SMAC-modulatory effects is warranted for its clinical consideration.
