Acetic acid enhances the effect of photodynamic therapy in gastric cancer cells via the production of reactive oxygen species.

Acetic acid is a major component of vinegar and is reported to have beneficial health effects. Notably, it causes oxidative stress and enhances the production of reactive oxygen species (ROS) in gastric cancer cells. ROS play important roles in cellular signal transduction, resulting in the regulation of protein expression and apoptosis. We previously reported that ROS upregulate heme carrier protein 1 (HCP1). Moreover, ROS increase the cellular uptake of porphyrins, which are precursors of heme and substrates for uptake by HCP1. Therefore, we hypothesized that photodynamic therapy (PDT) for cancer treatment using laser irradiation and photosensitizers, such as porphyrin, is enhanced via ROS produced by acetic acid. Herein, we used the rat gastric mucosal cells, RGM1, its cancer-like mutated cells, RGK1, and a manganese superoxide dismutase (MnSOD)-overexpressing RGK cell line, RGK-MnSOD. We confirmed that cancer-specific cellular uptake of porphyrin is increased upon acetic acid treatment and enhances the PDT cytotoxicity in RGK-1, not in RGM-1 and RGK-MnSOD. We believe that this occurs because of the overproduction of ROS and subsequent upregulation of HCP1 in cancerous cells. In conclusion, acetic acid can elevate the effect of PDT by inducing cancer-specific HCP1 expression via ROS production.

Elevated Production of Mitochondrial Reactive Oxygen Species via Hyperthermia Enhanced Cytotoxic Effect of Doxorubicin in Human Breast Cancer Cell Lines MDA-MB-453 and MCF-7.

Hyperthermia (HT) treatment is a noninvasive cancer therapy, often used with radiation therapy and chemotherapy. Compared with 37 °C, 42 °C is mild heat stress for cells and produces reactive oxygen species (ROS) from mitochondria. To involve subsequent intracellular accumulation of DOX, we have previously reported that the expression of ATP-binding cassette sub-family G member 2 (ABCG2), an exporter of doxorubicin (DOX), was suppressed by a larger amount of intracellular mitochondrial ROS. We then hypothesized that the additive effect of HT and chemotherapy would be induced by the downregulation of ABCG2 expression via intracellular ROS increase. We used human breast cancer cell lines, MCF-7 and MDA-MB-453, incubated at 37 °C or 42 °C for 1 h to clarify this hypothesis. Intracellular ROS production after HT was detected via electron spin resonance (ESR), and DOX cytotoxicity was calculated. Additionally, ABCG2 expression in whole cells was analyzed using Western blotting. We confirmed that the ESR signal peak with HT became higher than that without HT, indicating that the intracellular ROS level was increased by HT. ABCG2 expression was downregulated by HT, and cells were injured after DOX treatment. DOX cytotoxicity enhancement with HT was considered a result of ABCG2 expression downregulation via the increase of ROS production. HT increased intracellular ROS production and downregulated ABCG2 protein expression, leading to cell damage enhancement via DOX.

Nitric oxide regulates the expression of heme carrier protein-1 via hypoxia inducible factor-1α stabilization.

Photodynamic therapy (PDT) is a cancer therapy that capitalizes on cancer-specific porphyrin accumulation. We have investigated this phenomenon to propose the following three conclusions: 1) the mechanism underlying this phenomenon is closely related to both nitric oxide (NO) and heme carrier protein-1 (HCP-1), 2) NO inactivates ferrochelatase, and thus, the intracellular porphyrin levels in the cells are increased by the administration of an NO donor after 5-aminolevulinic acid treatment, 3) HCP-1 transports not only heme but also other porphyrins. Since NO stabilizes hypoxia-inducible factor (HIF)-1α, resulting in the upregulation of heme biosynthesis, HCP-1 expression can be increased by HIF-1α stabilization. In this study, we determined whether NO regulates HCP-1 expression by stabilizing HIF-1α expression. For this purpose, rat gastric cancer cell line RGK36 was treated with L-arginine or N6-(1-iminoethyl)-L-lysine (L-NIL). L-arginine treatment increased the intracellular NO concentration, and both HCP-1 and HIF-1α expression, while L-NIL treatment decreased them. Cytotoxicity of PDT was enhanced by L-arginine, following intracellular hemato-porphyrin dihydrochloride (HpD) accumulation. Both Cytotoxicity of PDT and HpD accumulation were decreased by L-NIL. The HCP-1 and HIF-1α expression, intracellular HpD accumulation and PDT cytotoxicity were decreased by 2-methoxyestradiol, which is a HIF-1α inhibitor. Moreover, these phenomena were not increased by a combination of both L-arginine and 2-Me. Thus, HCP-1 can be a downstream target of HIF-1α. These effects were also induced in the human gastric cancer cell line MKN45. Taken together, we conclude that HCP-1 expression is regulated by NO via HIF-1α stabilization.

Successful Long-term Management with a Single Administration of Tri-weekly Nab-paclitaxel in a Patient with Advanced Gastric Cancer with Peritoneal Dissemination.

Nanoparticle albumin-bound (nab)-paclitaxel has shown promising activity in advanced gastric cancer treatment. We herein report a case of advanced gastric cancer involving long-term management with a single administration of nab-paclitaxel. A 71-year-old man diagnosed with advanced gastric cancer with malignant ascites was treated with nab-paclitaxel as a second-line chemotherapy. He refused treatment continuation because of various severe toxicities in the first treatment cycle; he was therefore followed-up without any further treatments. Despite this, no disease progression was observed over 9 months. After progression, he received dose-dense paclitaxel, but he did not respond to this treatment and eventually died.