4-hexylresorcinol exerts antitumor effects via suppression of calcium oscillation and its antitumor effects are inhibited by calcium channel blockers

Abstract

Abstract. The bacterial dormancy-inducing factor 4-hexylresorcinol (4-HR) has been shown to have synergistic antitumor effects when used in combination with cisplatin. In the present study, 4-HR was used as a single agent in the squamous carcinoma cell line SCC-9. The results demonstrated that 4-HR suppressed SCC-9 cell proliferation compared to primary cultured gingival fibroblasts. 4-HR dose-dependently induced SCC-9 cell apoptosis as determined by caspase-3 activity, Annexin V expression, as well as by scanning and transmission electron microscopy. 4-HR inhibited intracellular calcium oscillation in both SCC-9 cells and normal human dermal fibroblasts. 4-HR-induced apoptosis was partly reversed by calcium channel blockers. Of note, 4-HR reduced the tumor mass formed by SSC-9 cell implantation in BALB/ cAnNCrj-nu/nu mice and mass size reduction was also partly reversed by the concomitant application of calcium channel blockers. Collectively, our results suggest that 4-HR has strong antitumor effects by inhibiting calcium channel oscillation and inducing apoptosis.

4-Hexylresorcinol Exhibits Different Characteristics to Estrogen

“…However, 4HR was cytotoxic to breast cancer cells regardless of ER expression ( Figure 1). 4HR is also cytotoxic to primary cultured oral melanoma cells [5] and SCC-9 cells [4] in the similar range of concentration to this study. However, its inhibitory effect is not significant in the normal human dermal fibroblasts [4].…”

“…4HR is also cytotoxic to primary cultured oral melanoma cells [5] and SCC-9 cells [4] in the similar range of concentration to this study. However, its inhibitory effect is not significant in the normal human dermal fibroblasts [4]. According to NIH toxicology report, 4HR has shown anticancer effects in various types of cancers [15].…”

“…Recently, other effects of 4HR have come into the limelight. 4HR has anticancer properties via inducing cancer cell apoptosis [4,5] and has been studied as an additive for graft materials because of its inhibitory effect on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway [6] and foreign body giant cell formation [7]. When 4HR is added to bone graft material, mineralization is increased [6,7].…”

“…However, there has been no convincing evidence for 4HR as a xenoestrogen. 4HR can induce cellular apoptosis in a dose-dependent and cellular type-dependent manner [4,18]. Thus, the inhibition of the spermatogenesis may be a complication of lethal dosage.…”

“…Many types of anticancer drugs may influence rapidly regenerated normal cells, including sperm [19]. 4HR also has anticancer effects [4,5]. The increased expression of estrogen-responsive promoter in MCF-7 cells may be a nonspecific response of 4HR or cross-activity mediated by an alternative signal pathway, excluding ER.…”