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| Author(s): |
Matheus da Silva Souza
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Carlos. |
| Institution: | Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) |
| Defense date: | 2024-04-11 |
| Examining board members: |
Adriano Defini Andricopulo;
Rafaela Salgado Ferreira;
Luma Godoy Magalhães;
Josué de Moraes;
Gustavo Henrique Goulart Trossini
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| Advisor: | Adriano Defini Andricopulo |
| Abstract | |
This thesis addresses the escalating global concern related to cancer, as indicated by the recent report from the International Agency for Research on Cancer, estimating 21.9 million cases and 11.4 million deaths in 2025. Prevalent among solid cancers are those affecting the lung, female breast, intestine, and prostate. Cellular invasion of surrounding tissue is a common event in tumor evolution, serving as an essential precursor to metastasis. This phenomenon involves cell migration, an activity mediated by the modulation of protein structures, notably microtubules (MTs), intracellular polymers crucial to eukaryotic cells. Recent advances in protein purification techniques have provided significant insights into the intrinsic dynamic properties of MTs, including their growth and shrinkage, processes regulated by molecular motors and associated proteins. This dynamic instability plays a crucial role in cell division and motility, central processes in the abnormal development of cancer. Within the scope of this doctoral study, titled \"Discovery of Novel Bioactive Ligands with Anticancer Properties\" (FAPESP grant #2018/25289-7), agents targeted at MTs were investigated for the treatment of metastatic triple-negative breast cancer and hormone-refractory prostate cancer. Among thirty-two evaluated compounds, two synthetic representatives, cis-2e and para-3d, stood out by exhibiting IC50 values ≤ 10 μM in breast and prostate tumor cell lines, respectively. These compounds not only circumvented resistance related to the overexpression of the βIII tubulin isoform in recombinant human cells but also demonstrated no toxicity in non-tumor cell lines, including local tissues and fibroblasts. The aforementioned compounds inhibited migration, invasion, and destabilized cell division, promoting nuclear fragmentation. Investigation into the mechanism of action revealed the inhibition of tubulin polymerization through allosteric interaction with the colchicine binding site or, vicinally, by blocking access to it. During a period abroad (FAPESP grant #2022/00219-1), under the supervision of Professor Dr. Anna Akhmanova (Utrecht University, Netherlands), facilities unavailable in Brazil were accessed. This opportunity enabled the quantification of dynamic instability parameters of MTs. Upon return, coupled with the experimental determination of the pharmacokinetic profile, an integrated analysis of the data was conducted, enabling the prioritization of lead compounds for future in vivo studies and proof of concept. (AU) | |
| FAPESP's process: | 18/25289-7 - Discovery of new bioactive ligands with anticancer properties |
| Grantee: | Matheus da Silva Souza |
| Support Opportunities: | Scholarships in Brazil - Doctorate |