Hepatocellular carcinoma (HCC) represents the fifth most common malignancy and the third most frequent cause of cancer death around the world (1
). Hepatitis B and C virus infections, exposure to aflatoxin, and excessive intake of alcohol have been identified as major risk factors of HCC. Surgery is the most effective option, but unfortunately the majority of patients with HCC are not amenable to surgery at the time of diagnosis. Presently, one of the main approaches in treating inoperable HCC is to use cytotoxic chemotherapy, but sometimes HCC is less sensitive to or becomes resistant to anticancer drugs after consecutive treatments; most tests failed to find a therapy which can produce a response rate >25% among hepatoma patients (2
). Despite recent progress in diagnosis and treatment, HCC is still diagnosed at an advanced stage where prognosis is poor. Important efforts should therefore be directed toward developing effective and less toxic chemotherapeutic strategies.
Aspirin (acetylsalicylic acid) is the best-known salicylate and belongs to the pharmacologic category of the nonsteroidal anti-inflammatory drugs (NSAIDs). Despite wide use being made for more than 100 years, clinical uses of aspirin have been changed over time and knowledge on its mechanisms of action and therapeutic entities continually evolve. During the first fifty years since it was developed, aspirin was primarily used as an analgesic, anti-pyretic, and anti-inflammatory agent based on its main mechanism of action of inhibiting prostaglandin synthesis. However, currently aspirin is more commonly used as an anti-thrombotic agent, in primary and secondary prevention of thromboembolic events. The suggestion that aspirin could be of benefit against cancer initially arose from the observation that tumor metastases were reduced in rats with thrombocytopenia (4
). Subsequently, prostaglandin concentration proved to be raised in rat colorectal tumor tissues (7
), which strengthened the expectation that anticancer benefit might be gained through the inhibition of cyclooxygenase (COX).
One obvious molecular target for aspirin is COX-2 which is the enzyme highly and rapidly induced in response to mediators of inflammation, growth factors, cytokines, or endotoxins, and is involved in cell proliferation and tumor promotion (9
). This is supported by the fact that aspirin can decrease the production of potentially neoplastic prostaglandins produced from COX-2-mediated catalysis of arachidonic acid (10
). The carcinogenic contribution of prostaglandins has generated much interest; their deleterious effects include promotion of cell survival, stimulation of cell proliferation, and promotion of angiogenesis (11
). These effects can also enhance cancer spread and thus underscore the cancer fighting potential of aspirin.
However, the anticancer effect of aspirin and NSAIDs cannot be solely explained by the inhibition of prostaglandin synthesis, since several NSAIDs have antiproliferative effects in cells that have no COX activity. High doses of aspirin have been reported to induce apoptosis through COX-independent mechanisms, by regulating several different targets (13
), such as 15-LOX-1
), a proapoptopic gene Par-4
), and an antiapoptopic gene Bcl-XL
). Additionally, NSAIDs including aspirin also induce apoptosis by means of the activation of caspases (17
), the activation of p38 MAP kinase (19
), release of mitochondrial cytochrome c
), and activation of the ceramide pathway (21
). These effects might not be universal to all cell types, however, and the dose range of aspirin needed in such COX-independent pathways could be higher than that for the inhibition of COX-2 (22
). Other mechanisms contributing to the potential anticancer effects of aspirin could be attributed to the upregulation of tumor suppressor gene, such as Bax
, and the downregulation of antiapoptotic gene, such as Bcl-2
). Apoptosis (programmed cell death) has been recognized as an important physiological event in the development and pharmacology of anticancer agents and cancer therapies (24
). In recent years, the regulation of apoptosis has become an area of extensive study in cancer research as the life span of both normal and cancer cells within a living system is regarded to be significantly affected by the rate of apoptosis (26
Raza et al
) recently demonstrated that aspirin treatment (5–10 μmol/ml) induced oxidative stress, cell cycle arrest in the G0/G1 phase, apoptosis, and mitochondrial dysfunction in HepG2 cells in vitro
. In this study, we evaluated the effects of aspirin on apoptosis induction in human hepatocellular carcinoma cell line in vitro
and antitumor activity in HepG2 cell xenograft of nude mouse model.