Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Abstract

Sorafenib (Nexavar, BAY43-9006), a bi-arylurea, is a newly established anti-

cancer drug and its functional attribute of cytotoxicity is based on the multi-

kinase inhibitory action. Here, we report yet another novel pathway in which

sorafenib can induce apoptotic cell death preferentially and efficaciously on an

experimentally proven drug- and radio-resistant human Hep G2 cells via a

mitochondria-dependent oxidative stress mechanism. A real time confocal

imaging assay revealed that sorafenib could rapidly provoke the production of

ROS plethorically, mainly concentrating in the mitochondria, albeit substantial

amounts of ROS could also be detected in cytosol and nucleus. The rapid

production of ROS could simultaneously induce intracellular glutathione (iGSH)

depletion. A nearly 90 % of iGSH was found to be depleted in one-hour period

after the cells received the drug treatment. Besides mitochondria, iGSH

depletion could also be detected in other cellular compartment including

cytoplasm and nucleus. Interestingly, we also demonstrated that sorafenib

could trigger mitochondrial Ca2+ overload. All these events compoundedly

serve as the final arbitrator to initiate lethal apoptotic process through the

release of cytochrome c and caspase 3 / 7 activation. Collectively, we provide

first evidence here that sorafenib can provoke an alternative pathway for

apoptosis induction of Hep G2 cells through a mitochondria-dependent

oxidative stress mechanism which is independent of original kinase inhibitory

attribute of the drug action. Most importantly, we also demonstrate that

sorafenib can effectively eradicate a highly drug- and radio-resistant HCC

cells. Thus, our data can provide the basis for a potential applicability of

sorafenib in a combined treatment modality.