Abstract
Photodynamic therapy (PDT) has emerged as a capable therapeutic modality for the treatment of cancer. PDT is a targeted cancer therapy that reportedly leads to tumor cell apoptosis and/or necrosis by facilitating the secretion of certain pro-inflammatory cytokines and expression of multiple apoptotic mediators in the tumor microenvironment. In addition, PDT also triggers oxidative stress that directs tumor cell killing and activation of inflammatory responses. However, the cellular and molecular mechanisms underlying the role of PDT in facilitating tumor cell apoptosis remain ambiguous. Here, we investigated the ability of PDT in association with hypericin (HY) to induce tumor cell apoptosis by facilitating the induction of reactive oxygen species (ROS) and secretion of Th1/Th2/Th17 cytokines in human hepatocellular liver carcinoma cell line (HepG2) cells. To discover if any apoptotic mediators were implicated in the enhancement of cell death of HY-PDT-treated tumor cells, selected gene profiling in response to HY-PDT treatment was implemented. Experimental results showed that interleukin (IL)-6 was significantly increased in all HY-PDT-treated cells, especially in 1 μg/ml HY-PDT, resulting in cell death. In addition, quantitative real-time PCR analysis revealed that the expression of apoptotic genes, such as BH3-interacting-domain death agonist (BID), cytochrome complex (CYT-C) and caspases (CASP3, 6, 7, 8 and 9) was remarkably higher in HY-PDT-treated HepG2 cells than the untreated HepG2 cells, entailing that tumor destruction of immune-mediated cell death occurs only in PDT-treated tumor cells. Hence, we showed that HY-PDT treatment induces apoptosis in HepG2 cells by facilitating cytotoxic ROS, and potentially recruits IL-6 and apoptosis mediators, providing additional hints for the existence of alternative mechanisms of anti-tumor immunity in hepatocellular carcinoma, which contribute to long-term suppression of tumor growth following PDT.
Highlights
Hepatocellular carcinoma (HCC) develops from an abnormal mass of tumor nodule and metastases to the adjoining parts of the liver eventually culminating in malignancy.[2,3] Accumulating lines of evidence suggest that HCC causes more than half a million new cases yearly.[3]
We evaluated the potential interaction between proinflammatory cytokines in the tumor microenvironment and the activation of apoptotic caspases in the presence of cytochrome complex (CYT-C) and BH3-interacting-domain death agonist (BID), pro-apoptotic factor in human hepatocellular liver carcinoma cell line (HepG2) cells following HY-Photodynamic therapy (PDT) treatment
To qualitatively test whether increasing concentrations of HY in PDT treatment could inhibit survival of HepG2 cells, we examined the morphological changes brought in by apoptosis following HY-PDT treatment using inverted light microscopy
Summary
HCC develops from an abnormal mass of tumor nodule and metastases to the adjoining parts of the liver eventually culminating in malignancy.[2,3] Accumulating lines of evidence suggest that HCC causes more than half a million new cases yearly.[3]. Photodynamic therapy (PDT) is a widely known effective therapeutic approach that requires a non-toxic photosensitizer (PS) drug and oxygen (O2) in concert with a harmless light source to facilitate selective destruction of tumorigenic cells.[6] A plethora of PS drugs, for instance, porfimer sodium (Photofrin II)[7] and 5-aminolevulinic acid,[8] have been widely. Inflammatory responses induced by reactive oxygen species (ROS) is believed to be the key priming event in the development of anti-tumor immunity.[12] The phototoxic reaction following HY-PDT initiates the release of proinflammatory mediators by triggering the release of interleukin (IL)-1a, IL-1b, Interferon (IFN)-g, IL-6, tumor necrosis factor (TNF)-a and certain other chemokines that provoke a strong inflammatory response in PDT-treated tumor cells.[13] Of note, IL-6, a pleiotropic cytokine implicated with barrier functions, is reported to trigger Th17 expansion. IL-6 synthesized following PDT is believed to mediate antitumor responses, providing additional secondary mechanisms of PDT-induced tumor cell killing
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