Chrysin enhances anticancer drug-induced toxicity mediated by the reduction of claudin-1 and 11 expression in a spheroid culture model of lung squamous cell carcinoma cells

Abstract

The aberrant expression of claudins (CLDNs), which are tight junctional proteins, is seen in various solid tumors, but the regulatory mechanisms and their pathophysiological role are not well understood. Both CLDN1 and CLDN11 were highly expressed in human lung squamous cell carcinoma (SCC). Chrysin, found in high concentration in honey and propolis, decreased CLDN1 and CLDN11 expression in RERF-LC-AI cells derived from human lung SCC. The phosphorylation level of Akt was decreased by chrysin, but those of ERK1/2 and c-Jun were not. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, inhibited the phosphorylation of Akt and decreased the expression levels of CLDN1 and CLDN11. The association between phosphoinositide-dependent kinase 1 (PDK1) and Akt was inhibited by chrysin, but the phosphorylation of PDK1 was not. Immunoprecipitation and quartz-crystal microbalance assays revealed that biotinylated-chrysin binds directly to Akt. The knockdown of CLDN1 and CLDN11 using small interfering RNAs increased the transepithelial flux of doxorubicin (DXR), an anthracycline anticancer drug. Similarly, both chrysin and LY-294002 increased DXR flux. Neither CLDN1 knockdown, CLDN11 knockdown, nor chrysin changed the anticancer drug-induced cytotoxicity in a two-dimensional culture model, whereas they enhanced cytotoxicity in a spheroid culture model. Taken together, chrysin may bind to Akt and inhibit its phosphorylation, resulting in the elevation of anticancer drug-induced toxicity mediated by reductions in CLDN1 and CLDN11 expression in RERF-LC-AI cells. We suggest that chrysin may be useful as an adjuvant chemotherapy in lung SCC.

CYP1B1 as a therapeutic target in cardio-oncology

“…Inhibition of CYP1B1 may interplay with these pathways leading to the chemo-sensitizing effects. [194] Isorhamnetin 17 [219] Protection from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [201] Potentiates DOX-induced toxicity in MCF-7, HepG2, and Hep2 cancer cells [201] Chrysin 24-270 [219,220] Protection from acute and chronic DOX-induced cardiotoxicity in vivo in rats [222,223] Enhanced cytotoxicity of DOX in a spheroid culture model of human lung squamous cell carcinoma [224], BEL-7402/ADM [225], lung cancer A549 cells [192], and human non-small-cell lung cancer cell lines [193] Apigenin 25 [219] Attenuated chronic DOX-induced cardiotoxicity in in vivo in rats and in vitro in rat cardiomyocytes [186][187][188] Augmented the cytotoxic effect of DOX against HepG2 cells [203], and DOX-resistant hepatocellular carcinoma cell line BEL-7402/ADM [204,218,226] Reverse chemo-resistance to DOX in DOX-resistant breast cancer cells (MCF-7/ADR) [198] Kaempferol 47 [219] Protected from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [227] Potentiated the cytotoxic effect of DOX in glioblastoma cells [205] Quercetin 77 [219] Protected rat and human cardiomyocytes and H9c2 cells from DOX-induced toxicity in vitro [176,188,189,199,228]. Protected from chronic DOX in rats [190,229] and mice [185] in vivo.…”

Endophytic fungus, Chaetomium globosum, associated with marine green alga, a new source of Chrysin

“…The IC 50 dose of chrysin on prostate carcinoma cells was determined to be 24.5 ± 0.1 µM after 48 h of treatment. The neoplastic potential of chrysin is very well known 8 – 14 .…”

“…Thus, inducing intrinsic and extrinsic apoptosis. Maruhashi et al 14 reported that chrysin enhances the anticancer potential of drugs in lung squamous cell carcinoma, suggesting its use as an adjuvant in chemotherapy.…”

Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

“…Chrysin decreased CLDN1 and CLDN11 expression in human lung SCC (RERF-LC-AI) cells. Chrysin alleviated p-Akt and inhibited PDK1 and Akt [ 170 ]. NiCl2 (Ni) induced migration and invasion in A549 and H1975 human lung cancer cells.…”