Elucidating the effects of sirolimus and sunitinib on nmu-induced rat breast carcinoma: in vitro and in vivo studies
Breast cancer tissue comprises genes altered, modified or/and mutated tissue. Nowadays, there are many options available for cancer remedy which includes surgery, chemotherapy, radiotherapy as well as immune-targeted therapy. A previous study found that combining drugs helps to improve tamoxifen eff...
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| Main Author: | |
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| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | http://eprints.usm.my/60713/1/MUHAMMAD%20SHAHIDAN%20BIN%20MUHAMMAD%20SAKRI-FINAL%20THESIS%20P-UD000117%28R%29-E.pdf http://eprints.usm.my/60713/ |
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| Summary: | Breast cancer tissue comprises genes altered, modified or/and mutated tissue. Nowadays, there are many options available for cancer remedy which includes surgery, chemotherapy, radiotherapy as well as immune-targeted therapy. A previous study found that combining drugs helps to improve tamoxifen effects towards breast cancer. Sirolimus also known as rapamycin, is a bacterial macrolide with anti-fungal properties, immunosuppressant and anti-angiogenic agent in targeted therapy. Sunitinib is a small molecule, multi-targeted receptor tyrosine kinases (RTKs) inhibitor. In this study, the effects of sirolimus and sunitinib on the breast cancer model were elucidated. Angiogenic factors which include VEGFR-2, PDGFR-β, mTOR, HIF-1α and STAT3 were studied. In addition, the correlation study of MVD with angiogenic expression was carried out as well. For in vivo model, a total number of twenty-four (24) female Sprague Dawley’s rats were obtained from ARASC USM Kubang Kerian at day 20 of age. The experiments and procedures towards the animal were conducted strictly in accordance with approval from the Animal Ethics Committee of USM guidelines of animal care and welfare. The breast tumour was induced by NMU and grouped into 4 groups (sirolimus, sunitinib, sirolimus+sunitinib and untreated). For in vitro model, MCF-7 and MDA-MB 231 cell lines were used representing aggressive types of breast cancer. The cell lines were treated with drugs and analyzed for proteins expression as well as apoptosis. Immunohistochemistry scoring for the entire treated groups showed a significant (P<0.05) reduction of angiogenic factors expressions compared to a control group. Gene analyses of sirolimus and sunitinib treated breast tumours showed significant (P<0.05) down-regulation of angiogenic factors compared to the untreated group. This indicated anti-angiogenesis properties of sirolimus and sunitinib suppressed angiogenic pathways. MVD study by using CD31 staining showed significantly reduced number of vascular obtained from the entire treated groups compared to the untreated group. A correlation study on MVD and angiogenic factors expression showed a positive correlation between angiogenic factors (VEGFR-2, mTOR, HIF-1α and STAT3) and MVD count. On the other hand, in vitro study of MCF-7 and MDA-MD 231 cell lines revealed that treatment with sirolimus and sunitinib significantly (P<0.05) reduced cell growth as well as proliferation rates compared to untreated at the IC50 dose. The result indicated sirolimus and sunitinib as well as sirolimus+sunitinib effectively inhibited proliferation of MCF-7 and MDA-MB 231 in the time and dose-dependent manner. Apoptosis study found a significant increase of apoptotic cells obtained in the entire treated groups. In conclusion, sirolimus and sunitinib as single agents represent potential effective anti-cancer drugs for breast cancer treatment which are proven at protein and gene analysis of in vivo and in vitro models while the combination of sirolimus and sunitinib showed a synergistic effect. |
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