Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences

Abstract

Abstract. Protoporphyrin IX (PpIX) levels are crucial to the antitumor action of photodynamic therapy (PDT). In the present study, the underling molecular mechanisms for the variation in PpIX levels in ovarian cancer cells were investigated. Five ovarian cancer cell lines were subcutaneously grafted onto the backs of nude mice. Once tumors had developed, 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA) was administered intraperitoneally and the tumor was irradiated twice/week. PpIX levels in the tumor were assayed using high-performance liquid chromatography. Enzymes involved in heme synthesis and degradation were screened using a microarray technique. Expression of the glutathione transferase Omega-1 (GSTO1) gene involved in the conversion of PpIX into heme in cells was quantified using the reverse transcription-quantitative polymerase chain reaction. In HTOA, HRA and DISS cells, PDT resulted in significant tumor shrinkage in comparison with the controls. In MCAS and TOV21G cells, no significant alterations in tumor growth were identified compared with the untreated cells. PpIX levels increased significantly in HTOA, DISS and HRA cells compared with in MCAS and TOV21G cells. A comparison of genetic profiles using PDT-sensitive DISS cells and PDT-resistant MCAS cells indicated that MCAS cells exhibited significantly increased levels of δ-aminolevulinate synthase (a rate-limiting enzyme in heme synthesis), heme oxygenase 2 (an enzyme that degrades heme into biliverdin), and biliverdin reductase B (an enzyme that reduces biliverdin into bilirubin) in comparison with DISS cells. The level of GSTO1 expression in HTOA, HRA and DISS cells was ~2.5-fold that in MCAS and TOV21G cells. Sensitivity to PDT is related to PpIX levels in cells. The results of the present study suggested that PpIX tends not to accumulate in PDT-resistant cells despite active heme synthesis and degradation, and that high levels of GSTO1 expression are associated with increased sensitivity to PDT. IntroductionThe standard treatment for ovarian cancer is surgery followed by anticancer therapy (1). A total of ~70% of advanced ovarian cancer recurs, so advanced ovarian cancer ultimately has a 5-year survival rate of between 30 and 40% (2). Ovarian cancer has the highest mortality rate among gynecological malignancies (3).Photodynamic therapy (PDT) has garnered attention as a novel therapy to reduce the tumor burden on a patient. PDT has been used to treat superficial esophageal cancer, early lung cancer and early gastric cancer (4-6). In gynecology, PDT has been used to treat early cancer of the cervix (7). Younger patients tend to opt to receive treatment that preserves fertility, and PDT may be such a treatment (7). Therefore, attention has focused on the usefulness of PDT in that regard. Unlike conventional approaches, PDT leaves the cervix intact, has a high cure rate, and does not hamper pregnancy or delivery following surgery (7).PDT is a therapy involving photosensitizers (or their precursors) with an affinity for tumors. The sp...

Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

“…Therefore, we bypassed this problem with a folate chemically coupled PS. Therefore, compared to existing photodynamic therapies for ovarian cancer [30], our study used a photosensitizer that could specifically target the ovarian cancer cells. In fact, most of the PDT studies have been conducted using 5-aminolevulinic acid methyl ester hydrochloride (5-methyl-Ala), a precursor of protoporphyrin IX (PpIX) in the heme metabolic pathway [31].…”

Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy

“…Oxidative stress-related proteins, such as superoxide dismutase [ 94 ], catalase [ 95 ], and NO synthase [ 96 ], are reported to affect PDT sensitivity. Glutathione and related proteins, such as glutathione peroxidase, glutathione-S-transferase, glutathione transferase omega-1, and glutathione synthase, are also thought to be associated with cell resistance to PDT [ 94 , 97 , 98 ]. Heme oxygenase-1 (HO-1) is an inducible cytoprotective enzyme that protects cells from oxidative stress, and its expression is induced by PDT [ 99 ].…”

A Surgical Pen-Type Probe Design for Real-Time Optical Diagnosis of Tumor Status using 5-Aminolevulinic acid

“…The characteristic of 5-ALA fluorescence contrast diagnosis has been formally approved by the US FDA [17,18]. Therefore, it can be applied to the diagnosis of gliomas, brain cancer, breast cancer, colonic mucosa, and ovarian cancer [1]- [5].…”

“…The 5-aminolevulinic acid (5-ALA) fluorescence dye is used to assess the condition of tumor removal in gliomas, brain cancer, breast cancer, colonic mucosa, and ovarian cancer [1]- [5]. In particular, malignant tumors are complex and composed of tumors and blood vessels.…”