One of the most lethal types of tumor is glioblastoma, as few drugs are effective in combating this misaligned growth of glial cells, which make up brain tissue. The current standard of care is surgical removal of the tumor, followed by temozolomide chemotherapy, radiotherapy, and nitrosoureas (such as lomustine). Although there has been some improvement in patient survival over the years, the poor prognosis remains, as these tumor cells have a very high capacity to resist existing drugs and often grow back after surgery.
Now, a study published in the journal Scientific Reports has shown promising results from two substances that managed to inhibit the proliferation of these tumor cells. For the in vitro test, 12 compounds generated as by-products during the total synthesis of apomorphine hydrochloride (APO) were evaluated. Two of them, called A5 (isoquinoline derivative) and C1 (aporphine derivative), have been shown to promote the death of glioblastoma cells. In addition, they managed to block the formation of new tumor stem cells and potentiated the effect of temozolomide, currently the main chemotherapeutic used in the treatment.
“More studies are needed to better characterize the action in tumor and normal cells, but the results obtained suggest a potential therapeutic application of these compounds as new cytotoxic agents useful in the control of glioblastomas”, explains Dorival Mendes Rodrigues-Junior, from the medical biochemistry department and microbiology at the University of Uppsala, Sweden, one of the authors of the article.
To design the study, the researchers focused on obtaining apomorphine hydrochloride, which involves a series of sequential chemical reactions, in which each step generates a compound that is consumed in the next step. In previous research, the group had evaluated the degree of effectiveness of 14 of these compounds in head and neck epidermoid cancer cells.
Both the A5 and the C1, also on that occasion, had shown promise and the option was to expand the tests. “Given the relevance and urgency of identifying new therapeutic substances that may be useful for the treatment of glioblastoma, we evaluated the same panel used in the previous study, but now for this other type of tumor”, explains Rodrigues-Junior.
The project on molecular markers for head and neck squamous cell carcinoma is supported by Fapesp and involves another author who also signed the most recent publication, André Vettore, from the Department of Biological Sciences at the Federal University of São Paulo (Unifesp), Diadema campus.
“This study presents interesting results, but they are just the first steps of a long journey. This potential usefulness of compounds A5 and C1 in the control of glioblastoma cells now needs to be analyzed in in vivo models, as well as having their effects evaluated in neural cells non-tumorigenic”, warns Vettore.
For the researcher, if the results obtained in these trials are promising, it is possible to assume that, in the future, the efficacy will be evaluated in clinical studies. “Following all the steps, these compounds may finally be useful in the treatment of patients affected by glioblastoma”, he says.
Bioactive natural products
The study was designed to evaluate the in vitro antitumor activities of 12 aromatic compounds obtained as intermediates in the total synthesis of apomorphine. This alkaloid substance interacts with the dopamine pathway and is already widely used to control motor changes caused by Parkinson’s disease.
Alkaloids represent one of the best-known classes of natural products with multiple pharmacological properties and are studied for their anticonvulsant, antiplatelet, anti-HIV, dopaminergic, antispasmodic and anticancer actions.
Fapesp encourages studies with these substances through a project carried out at Unifesp’s Chemistry Department, in Diadema, under the coordination of Cristiano Raminelli, another author of the publication in Scientific Reports. Haifa Hassanie, Gustavo Henrique Goulart Trossini, Givago Prado Perecim, Laia Caja and Aristidis Moustakas also signed the study.
The article Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity can be read here.
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