Flunarizine, a drug approved for treating migraine and vertigo, exhibits cytotoxicity in GBM cells.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a poor prognosis. The current treatment regimen, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, is still not curative. Therefore, there is an emerging need to develop a drug to treat GBM or synergistic enhance TMZ effect on GBM cells. Flunarizine (FLN), a drug approved for treating migraine and vertigo, was analyzed for its cytotoxicity and synergistic effect with TMZ on GBM cells in this study. Cell proliferation, clonogenic assay, flow cytometry, and Western blotting were used to determine the effects of FLN on three GBM cells, U-87 MG, LN-229, and U-118 MG cells. We found that FLN induced GBM cell death. FLN also interfered with U-87 MG cell cycle progression. Flow cytometric analysis showed an increase of apoptotic cells after FLN treatment. Caspase 9, caspase 3, and Poly (ADP-ribose) polymerase (PARP) activation were involved in apoptosis induction in U-87 MG and LN-229, suggesting the possible involvement of an intrinsic apoptotic pathway. We found that FLN treatment inhibited Akt pathway activation in U-87 MG cells, and synergistically increased the cytotoxicity of three GBM cells when combined with TMZ treatment. In conclusion, our current data suggested that FLN inhibited cell viability by inducing apoptosis. FLN inhibited Akt activation and enhanced the sensitivity of GBM cells to TMZ. These findings may provide important information regarding the application of FLN in GBM treatment in the future.

Lactobacillus acidophilus-Fermented Germinated Brown Rice Suppresses Preneoplastic Lesions of the Colon in Rats.

Colorectal cancer (CRC) is a cancer associated with chronic inflammation. Whole grains and probiotics play a protective role against CRC. Fermented grains are receiving increased attention due to their anti-inflammatory and anti-cancer activities. Our previous study found that a combination of germinated brown rice (GBR) with probiotics suppressed colorectal carcinogenesis in rats. However, the cancer-preventive effect of probiotic-fermented GBR has not been reported. This study investigated the preventive effect and possible mechanism of GBR fermented by Lactobacillus acidophilus (FGBR) on colorectal carcinogenesis in rats induced by 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS). DMH/DSS treatment induced preneoplastic aberrant crypt foci (ACF), elevated serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß, as well as decreased pro-apoptotic Bax expression. GBR and FGBR reduced the primary ACF number and decreased TNF-α, IL-6 and IL-1ß levels. GBR and FGBR at the 2.5% level increased pro-apoptotic cleaved caspase-3 and decreased anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. FGBR at the 2.5% level further reduced the number of sialomucin-producing ACF (SIM-ACF) and increased Bax expression. These results suggest that FGBR may inhibit preneoplastic lesions of the colon via activating the apoptotic pathway. This fermented rice product may have the potential to be developed as a novel dietary supplement for CRC chemoprevention.

Piperlongumine induces autophagy in biliary cancer cells via reactive oxygen species-activated Erk signaling pathway.

Biliary cancer (BC) is an aggressive neoplasm with high mortality. BC can be categorized into three groups: Intrahepatic cholangiocarcinoma (CCA; also known as bile duct cancer), extrahepatic cholangiocarcinoma and gallbladder cancer. Due to its heterogeneity and aggressiveness, the response to current chemotherapy and radiotherapy methods in patients with BC is poor. Therefore, there is an urgent requirement to develop drugs to treat BC. Piperlongumine (PL), a naturally occurring small molecule isolated from Piper longum L., exhibits anticancer activity by inducing reactive oxygen species (ROS) production. In the present study, the effects of PL on cell proliferation, cell cycle, apoptosis and autophagy in BC cells were investigated. PL induced BC cell death in a concentration­ and time­dependent manner by inducing ROS production. PL induced cell cycle arrest in CCA cells (HuCCT­1) and gallbladder cancer cells (OCUG­1) cells, but with distinct cell cycle distribution profiles. PL caused G2/M cell cycle arrest in HuCCT­1 cells, and G0/G1 cell cycle arrest in OCUG­1 cells. PL induced apoptosis and autophagy; PL treatment induced accumulation of LC3­II in a concentration­ and time­dependent manner. The Erk signaling pathway appeared to be involved in autophagy induction. Application of the ROS scavenger, N­acetyl­l­cysteine, to BC cells attenuated the cell death, cell cycle arrest, apoptosis and autophagy induced by PL treatment. These findings indicated that PL may be a potential agent for BC treatment in the future.