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Abstract

Hepatotoma is the leading type of primary liver cancer in adults and third cause of death in the world. Hydroxytyrosol is a natural phenol existing in olive (Olea europaea L.). Hydroxytyrosol is the chief ingredient of olive oil, which was early deemed to be the most robust antioxidant in olive oil. Hydroxytyrosol is known to inhibit various types of cancer by different methods. This study was aimed to delineate the action of hydroxytyrosol on viability and [Ca²⁺]_i in HepG2 hepatoma cells. Fura-2 was used to detect [Ca²⁺]_i, and WST-1 assays were applied to explore cell cytotoxicity. Hydroxytyrosol elicited [Ca²⁺]_i raises. Eliminating external Ca²⁺ diminished the Ca²⁺ signal by 30%. Hydroxytyrosol-evoked Ca²⁺ influx was diminished by 20% by three inhibitors of store-operated Ca²⁺ channels and by a protein kinase C activator and an inhibitor. In the absence of Ca²⁺, thapsigargin eradicated hydroxytyrosol-provoked [Ca²⁺]_i raises. Suppression of phospholipase C (PLC) with U73122, a PLC inhibitor, did not inhibit hydroxytyrosol-elicited [Ca²⁺]_i raises. Hydroxytyrosol reduced cell viability. This cytotoxic action was not reversed by preincubation with BAPTA/AM, a cytosolic Ca²⁺ binder. In sum, in HepG2 hepatoma cells, hydroxytyrosol elicited [Ca²⁺]_i raises by provoking PLC-unrelated discharge of Ca²⁺ from ER and Ca²⁺ influx through PKC-sensitive store-operated Ca²⁺ entry. In addition, hydroxytyrosol elicited Ca²⁺-dissociated cytotoxicity.

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