Changes of protein expression of platinum resistance indicators under the influence of hyperthermia during the HIPEC procedure in recurrent ovarian cancer

Abstract

Ovarian cancer relapse and death are usually caused by acquired drug resistance. The mechanisms of platinum resistance are multifactorial. Excision repair cross-complementation group 1 (ERCC1) is a protein critical in removing platinum-induced DNA lesions. Microsatellite Instability (MSI) is present in a substantial proportion of ovarian cancers but knowledge about its clinical value is limited. Hyperthermia, one more promising treatment agent, delays the repair of DNA damage. Hyperthermic intraperitoneal chemoperfusion (HIPEC), which has been actively studied in recent years as a possible addition to therapy for advanced stages of epithelial ovarian cancer. Material and methods. The study was retrospective, it included a total of 16 patients with stage IIIC epithelial ovarian cancer. For various reasons, these patients underwent suboptimal cytoreductive surgery with HIPEC + Second-look surgery with complete / optimal cytoreduction (6 patients) or relaparotomy with biopsy of residual disease due to surgical complications in 2–4 weeks interval. Immunohistochemical investigation of ERCC1 and MLH-1 expression were performed for the histological samples obtained from pre- and post HIPEC metastatic tumor tissue on the first and second surgical interventions. Conclusions. DNA repair pathways are one of the most important factors of platinum drug resistance formation. Hyperthermia during HIPEC procedure leads to decrease in the efficiency of DNA repair pathways by reducing the expression of ERCC1 and MMR proteins. These changes may determine the proven effectiveness of HIPEC procedure with cytoreduction after NACT (which may lead to secondary platinum drug resistance formation) by overcoming platinum resistance.

Рецидив раку яєчників і подальша смерть зазвичай спричинені набутою медикаментозною резистентністю. Механізми резистентності до платини багатофакторні. Шляхи репарації ДНК є одним із найважливіших факторів формування стійкості до препаратів платини. Гіпертермія під час процедури HIPEC призводить до зниження ефективності репарації ДНК шляхом зменшення експресії ERCC1 (з 57,56% клітин до 5% клітин – p < 0,05) та білків MLH-1 (з 9,11% клітин до 0% клітин – p < 0,05). Цей механізм подолання вторинної резистентності до препаратів платини обґрунтовує ефективність процедури HIPEC з циторедукцією після неоадʼювантної хіміотерапії.