Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O6-methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has been shown to have antiproliferative effects on various cancer cell lines. DHT has also been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT, P-glycoprotein, AKT, p65, and IlkB levels after singular and combinatorial treatment. DNA microarray was used to gauge gene expression and miRNA levels. Solute clearance of the blood-brain barrier was analyzed using a co-culture model system and confocal microscopy. DHT had a selectively cytotoxic synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein expression and protein levels. In addition, the NFkB complex was sensitive to combinatorial treatment, while AKT activity and gene expression was downregulated in response to treatment. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood–brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma.

Citation Format: Varun Kumar, Donna Leonardi. The chemosensitizing and oncolytic effects of Dihydrotanshinone in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2860.