Redox-related Molecular Mechanism of Sensitizing Colon Cancer Cells to Camptothecin Analog SN38

Abstract

Background/Aim: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP). Materials and Methods: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests. Results: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters -up-regulation of SLCO1B1 and retention of SN38 in the cells. Conclusion: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.Colorectal cancer is one of the most aggressive cancers (1). It is a widespread malignant disease in industrialized countries. The clarification of its mechanism and the development of new therapeutic methods and techniques are of great interest nowadays.Chemotherapy with the semisynthetic pro-drug irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; CPT-11) is one of the common therapeutic strategies in colorectal cancer. In 1996, irinotecan was approved for clinical use both in the United States and Japan (2, 3). So far, it is widely used in first-and second-line treatment of advanced colorectal cancer. Irinotecan is a water-soluble camptothecin analogue -alkaloidal derivative from Chinese tree plant (Camptotheca acuminata) (4). Bioactivation of CPT-11 in cells to its active metabolite SN38 is performed via a carboxylesterase-catalyzed reaction (4). SN38 has a 100-to 1,000-fold greater anticancer activity than irinotecan (4, 5). Furthermore, SN38 is a potent DNA topoisomerase I (Topo-I) inhibitor, acting via formation of a stable Topo-I-DNA cleavable complex, subsequently causing DNA damage (resulting in cell cycle arrest and/or cell death by apoptosis) (4).It is widely accepted that apoptosis is an energy-dependent process, which is characterized by early release of mitochondrial cytochrome c; activation of apoptotic protease activating factor 1 (APAF-1); and activation of caspase-9, ending with degradation of cellular proteins, such as PARP, laminin, and β-actin (hallmarks for programmed cell death). Induction of apoptosis is dependent on the cellular redoxstatus, which is essential for cell viability. Cellular redoxstatus is defined as a balance between the main endogenous

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“…As reported previously, the generation of ROS is associated with tumor cell death with both DSF [35] and SN-38 [36] treatments. We wanted to evaluate whether treatment with the DSF+SN-38 combination would increase ROS generation.…”

A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer

“…For example, triterpene saponin ardisiacrispin B and epunctanone exerted cytotoxic effects partly via ferroptosis in resistant HCT116 p53−/− colon adenocarcinoma cells ( 6 , 7 ). By inducing ferroptosis and apoptosis, electroporation increased the sensitivity of CC cells to camptothecin analog SN38 ( 8 ). Omega-3 polyunsaturated fatty acids (n-3 PUFA) and highly fermentable fiber may induce ferroptosis to reduce the risk of colorectal cancer ( 9 ).…”

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“…In vitro experiments showed that EP sensitized colon cancer cells to the camptothecin analogue, SN38, by changing the expression of ABC transporters and disrupting the integrity of the cytoskeleton. The chemosensitizing effect was due to the induction of oxidative stress and apoptotic/ferropoptotic cell death [ 101 ]. Promising results from in vivo experiments highlighted the importance of the use of ECT in the treatment of colon cancer, where electropermeabilization significantly increased the intratumoral content of bleomycin and cisplatin [ 102 ].…”