Demethoxycurcumin analogue DMC-BH inhibits orthotopic growth of glioma stem cells by targeting JNK/ERK signaling

Abstract

Glioma stem cells (GSCs) play an important role in glioblastoma resistance to conventional therapies and disease recurrence. Here, we assessed the therapeutic effect of a demethoxycurcumin analogue, DMC-BH, on GSCs, and investigated the underlying mechanisms. Our in vitro data demonstrate that DMC-BH inhibits GSC proliferation, and induces apoptosis and autophagy in GSCs. In addition, our results show that DMC-BH effectively crosses the blood-brain barrier to inhibit the growth of intracranial GSC tumors in vivo. DMC-BH significantly increased phosphorylation levels of JNK, ERK and c-Jun in GSCs. Inhibition of JNK and ERK activities reversed the pro-apoptotic effect of DMC-BH in GSCs, indicating that the DMC-BH-induced apoptosis in GSCs is mediated via the JNK/ERK signaling pathway. These results suggest that DMC-BH could potentially serve as a effective therapy against GSCs that acts by targeting the JNK/ERK signaling pathway.

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…The GSH redox system plays an important role in cell survival and apoptosis [ 52 , 53 , 54 ], and inhibition of HPGDS was found to result in a downregulation of the GSH levels and a reduction in cellular drug resistance. Considering that the JNK pathway plays an important role in promoting apoptosis in glioma, and a variety of GSTs can regulate the activation of the JNK signaling pathway [ 42 , 55 , 56 ], we speculate that the resistance-promoting function of HPGDS is partly attributable to the inhibition of apoptosis resulting from downregulated activation of the JNK pathway. In this study, inhibition of HPGDS led to significant activation of JNK phosphorylation, and interference with the activation of the JNK pathway reversed the reduction in cell drug resistance caused by inhibition of HPGDS, indicating that HPGDS functions similarly to other GSTs in regulating the activation level of apoptotic pathways.…”

Promising antitumor effects of the curcumin analog DMC-BH on colorectal cancer cells

“…Six-week-old male nude mice were subcutaneously inoculated with 5 × 10 6 HCT116 or HT-29 cells in the left flank. When the xenograft volume reached 75 mm 3 , DMC-BH or curcumin (20 mg/kg) was administered intraperitoneally once a day for 15 days [ 6 , 30 , 31 ]. Tumor volume was measured every other day with a caliper and calculated using the following formula: V (mm 3 ) = Length ×Width 2 × 0.5.…”

“…Therefore, controlling the recurrence and metastasis of CRC is the key to improving the prognosis and quality of life of patients. DMC-BH is a compound that was obtained by introducing a water-soluble pyrrolidine fragment into the benzene ring of the natural compound curcumin to improve its water solubility and has antiglioma effects [6,7]. Curcumin is a well-known plant-derived polyphenol and has been shown to inhibit the progression of certain cancer cells, including CRC [8,9].…”

A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

“…Despite its poor bioavailability, curcumin has been identified to suppress medulloblastoma growth in vivo through its HDAC inhibition activity (23). In addition, curcumin has been proven to inhibit cell proliferation, invasion, angiogenesis, and metastasis of GBM in our previous work; thus, we hypothesis that curcumin could be developed as an HDAC inhibitor for the treatment of GBM (24)(25)(26). However, the poor HDAC inhibition activity and selectivity impeded the direct application of curcumin as an HDAC inhibitor for the treatment of GBM.…”