Abstract
Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.
Highlights
Gliomas are the most common and lethal malignant primary brain tumors in humans
KA-induced apoptosis of U87 cells The externalization of phosphatidylserine, which is a hallmark of apoptotic cells, has been observed in alternative types of programmed cell death
The annexin V/propidium iodide (PI) assay revealed that the number of annexin V- and annexin V/PI-positive cells www.bjournal.com.br increased after 48 h of treatment with 50 and 70 mM KA
Summary
Gliomas are the most common and lethal malignant primary brain tumors in humans. Glioblastoma multiforme is the highest grade, the most aggressive and the most frequent glioma [1]. Because gliomas are characterized by a diffuse infiltrative growth into the surrounding brain tissue, the complete surgical resection of glioblastoma multiforme tumors is virtually impossible [2]. High-grade gliomas exhibit only limited sensitivity to multimodal treatment with radiotherapy and chemotherapy, which in large part is caused by the inherent and potent resistance of the tumor cells to apoptosis [3]. Overcoming apoptotic resistance through the reactivation of apoptosis in malignant cells will be important for the development of novel glioma therapies. Several natural products derived from plants have been reported to prevent tumorigenesis and suppress the growth of established tumors. Research has intensely focused on the identification of new herbal medicines and on the mechanisms behind the anti-tumor properties of existing natural products [4]
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