Glioma is the most prevalent and aggressive tumor of the Central Nervous System (CNS). According to the investigations on cells, gliomas could be divided into oligodendroglioma, astrocytoma, mixed gliomas (oligo-astrocytomas), and ependymomas [1]. The World Health Organization (WHO) has categorized gliomas under four grades subtype. Grades I and II are classically investigated as low-grade gliomas, while grade III and IV tumor types are considered as high-grade gliomas. Glioblastoma Multiform (GBM, grade IV astrocytoma) is a competitive and fast-growing tumor, with an average survival of 12–14 months after initial diagnosis [2]. This makes the discovery of an efficient therapeutic approach as vital in treating this disease [3]. Glioma cells' high development and diminished apoptosis potentials are chiefly reliant upon hereditary intensifications or transformations and changes in pro-apoptotic and oncogenic gene expression [4]. The idea of molecular-based therapeutic approaches for GBM tumors is dependent on probable pharmacological or genetic changes in the main molecular signaling pathways such as the phosphatidylinositol-3-kinase (PI3K)/AKT pathway to reduce GBM proliferation and increase cells’ sensitivity to conventional chemotherapeutics [5,6]. PI3K/AKT signaling possesses complicated nature in different cellular processes related to normal growth and cellular hemostasis, however, its role in many features associated with cancer, for example, variations types, proliferation, the transition of epithelial-mesenchymal, stemness, or angiogenesis has been approved, so far [7]. Abnormal PI3K/AKT molecular signaling in GBM has commonly been reported being contributed to enhance GBM survival and chemoresistance [7]. To find more efficient therapeutic approaches, it is vital to regulate the underlying processes in GBM chemoresistance to understand the molecular mechanisms involved in this progress.

The last decades have witnessed an increased tendency to implement natural compounds and polyphenols in cancer treatment for many purposes ranging from prevention, treatment to reversing drug resistance [8]. Resveratrol (3,5,4′-trihydroxy-trans-stilbene), present in red wine, grapes, soy, peanuts, etc., is one the most extensively studied polyphenolic compounds in cancer treatment with notable pro-apoptotic, anti-inflammatory, and anti-proliferative functions [9]. In GBM, different mechanisms are responsible for the anti-cancer effects of resveratrol among which, the notable ones are the regulation of cell proliferation and cell cycle progression, oxidant system, apoptosis pathways, and autophagy [10].

Resveratrol has also been used in combination with radiation therapy and chemotherapy. In addition, different studies evaluated the efficacy of resveratrol, in combination with numerous chemotherapeutic agents, in increasing the sensitivity of cancer cells to these agents and have found promising results [11]. Therefore, this study tries to evaluate the effects of resveratrol in reversing doxorubicin resistance by targeting PI3K/AKT signaling pathway in U87MG/DOX cells.