Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemo-sensitization towards oxaliplatin through inducing pro-death autophagy.

Hypericin is an endoplasmic reticulum (ER)-located photosensitizer, which causes oxidative damage to ER during photodynamic therapy (PDT). Hypericin-mediated PDT (HY-PDT) has been confirmed to enhance chemo-sensitivity of oxaliplatin (L-OHP) in colon cancer cells. The present study reveals that autophagy plays a key role in chemosensitization during HY-PDT. We proved pro-death autophagy was required for sensitization and HY-PDT/L-OHP antitumor synergism. High dosage of HY-PDT induced autophagic cell death; while low dose of HY-PDT predominantly triggered protective autophagy and promoted cell proliferation. Low dose of HY-PDT reduced the cytotoxicity of L-OHP in oxaliplatin-resistant colon cancer cells. Different level of autophagy therefore contributed to the opposite effect of HY-PDT on cell fate and chemo-sensitivity. Furthermore, we revealed the role of CHOP as a regulator connecting pro-survival and pro-death autophagy under ER damage. High dose of HY-PDT induced massive ROS generation and severe ER stress, which then led to induction of CHOP. CHOP thereby activated CHOP/TRIB3/Akt/mTOR cascade and triggered autophagic cell death. Additionally, when apoptotic pathway was blocked, cells treated with high dose of HY-PDT preferentially underwent death through autophagic pathway. On the other hand, suppression of autophagy made cells more vulnerable to apoptosis under low dose of HY-PDT. These results provided new evidences for the clinical application of ER-targeting PDT in modifying chemosensitivity of colorectal cancer therapy.

3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells.

Compared to normal cells, most cancer cells produce ATP by glycolysis under aerobic conditions rather than via the tricarboxylic acid cycle (TCA). This study is intended to determine whether 3B, a novel photosensitizer, can inhibit glycolysis and inflammation in breast cancer cells. We showed that 3B had the ability to repress glucose consumption as well as the generation of ATP, lactate and lactate dehydrogenase. 3B-PDT not only inhibited the expression of IL-1ß and IL-6 but also affected the JAK-STAT3 inflammatory pathway in vitro. The present study showed that 3B featured a significant inhibitory effect on the expression of microRNA-155-5p and SOCS1 might serve as a target gene. In vivo studies revealed that 3B inhibited tumor growth and exhibited almost no side effects. Therefore, through the anti-glycolytic effect and breakage of the JAK/STAT3/SOCS1 feedback loop via miR-155-5p, 3B may potentially serve as a potential therapeutic agent against breast cancer.

p38 mitogen-activated protein kinase inhibition modulates nucleus pulposus cell apoptosis in spontaneous resorption of herniated intervertebral discs: An experimental study in rats.

The present study was performed to investigate the role of p38 mitogen­activated protein kinase (MAPK) in the resorption of herniated intervertebral discs in 30 rats. In the non­contained and p38 MAPK inhibition (p38i) groups, two coccygeal intervertebral discs (IVDs) were removed and wounded prior to relocation into the subcutaneous space of the skin of the back. In the contained group, the cartilage endplates maintained their integrity. Furthermore, SB203580 was injected intraperitoneally into the p38i group, whereas saline was injected into the other two groups. In the non­contained group, the weight of the relocated IVDs decreased to a greater extent over time when compared with the contained and p38i groups. Phosphorylated p38, tumor necrosis factor­α, and interleukin­1ß were observed to exhibit higher expression levels in the non­contained group compared with the contained and p38i groups, at weeks 1 and 4 post­surgery. The expression level of caspase­3 and the densities of apoptotic disc cells were significantly higher in the non­contained group compared with the contained and p38i groups at 4 weeks post­surgery. In conclusion, p38 MAPK induces apoptosis in IVDs, while also accelerating the resorption of the relocated IVDs. Thus, p38 MAPK may be important in spontaneous resorption of IVDs.

Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism.

The resistance to oxaliplatin (L-OHP) is a major obstacle to ideal therapeutic outcomes in colorectal cancer. Photodynamic therapy (PDT) induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a well-studied photosensitizer. In this study, we explored the role of hypericin-mediated PDT (HY-PDT) in sensitizing human colorectal cancer cells towards L-OHP. Pre-treatment with HY-PDT enhanced the anti-tumor activity of L-OHP via decreasing drug efflux and increasing platinum accumulation. Further research showed that HY-PDT-mediated resensitization of resistance cells towards L-OHP was dependent on regulation of MRP-2, instead of p-gp. HY-PDT was also found to inhibit intracellular glutathione (GSH) and Glutathione S-transferase (GST), suggesting the involvement of GSH-related detoxification in the sensitization effect. Additionally, enhanced DNA double-strand breaks (DSBs) was observed following HY-PDT/L-OHP combined treatment. HY-PDT lowered the removing rate of platinum from DNA and down-regulated the expression of ERCC1 and XPF, two critical enzymes involved in nucleotide excision repair (NER) pathway. GSH monoethyl ester (GSH-EE) antagonized HY-PDT-induced ROS and repressed sensitization to platinum. Taken together, HY-PDT mediated sensitization of L-OHP in human colorectal cancer is mediated by ROS, whose mechanism involves affecting drug efflux, GSH-related detoxification and NER-mediated DNA repair.

3B, a novel of photosensitizer, exhibited anti-tumor effects via mitochondrial apoptosis pathway in MCF-7 human breast carcinoma cells.

Photodynamic therapy (PDT) has been recognized as an innovated therapeutic modality for the treatment of various cancers. In this study, we evaluated the anticancer effect of a new photosensitizer 3B in breast cancer, which was considered one of the most common cancers in women worldwide. Here, we determined the effect of 3B not only on the cell growth, apoptosis, and Bcl-2 signal pathway in vitro but also on the anti-cancer effect in nude mice in vivo. Our results showed that 3B was primarily accumulated in mitochondria, increased the level of ROS, induced apoptotic cells death via Bcl-2 family, and its activity could be blocked by the caspase inhibitor (Z-VAD-FMK). In vivo study, 3B made a significant opening inhibition of tumor growth and showed drug toxicity hardly. TUNEL assay indicated that PDT group showed more positive cells (green) than other groups. These data supported that 3B might develop as potential therapeutic drug for the treatment of breast cancer.