Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells

Abstract

Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM.

Cardamonin enhances the anti-proliferative effect of cisplatin on ovarian cancer

“…Several studies have reported that cardamonin is able to inhibit the expression of Bcl-2, Survivin and induce apoptosis (22,41). Furthermore, the mTOR inhibitor CCI-779 decreases the expression of anti-apoptotic proteins and restores the sensitivity of cisplatin-resistant small cell lung cancer cells to cisplatin (42).…”

“…Cardamonin inhibits a number of signaling pathways, including c-Jun N-terminal kinase, nuclear factor-κB, and signal transducer and activator of transcription 3 (21,22). Combined with doxorubicin, cardamonin sufficiently prevents the enrichment of drug-resistant triple negative breast cancer stem cells and retards tumor growth (23).…”

Preclinical pharmacokinetics and ADME characterization of a novel anticancer chalcone, cardamonin

“…[54] • Suppresses existing breast CSCs after chemotherapeutic drug treatments, prevents the enrichment of new CSCs during chemotherapeutic drug treatments and enhances the efficacy of chemotherapeutic drugs by reducing tumour burden as well as the CSC pool in vivo. [55] Effect on angiogenesis [55] Effect on angiogenesis…”

“…[11] • Induces apoptosis by suppressing STAT3 signalling pathway in glioblastoma stem cells. [55] Effect on angiogenesis…”

Cardamonin as a potential treatment for melanoma induces human melanoma cell apoptosis

“…2',4'-dihydroxy-6'-methoxychalcone (cardamonin) is a natural chalcone compound that is extracted from members of the Zingiberaceae family (7). It may increase cell apoptosis in several tumors, including nasopharyngeal carcinoma, prostate cancer and glioblastoma (8)(9)(10). Cardamomin may be effective via multiple signaling pathways, including nuclear factor (NF)-κB, signal transducer and activator of transcription 3 and mammalian target of rapamycin pathways (8,10,11).…”