Abstracts of Theses Approved for MSc Degrees at the Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait: Abstracts

摘要

Manganese porphyrins (MnP) are superoxide dismutase syn-thetic mimetics that accumulate within cancer cells along with ascorbate and generate hydrogen peroxide when combined. MnP differ in their reduction potential, lipophilicity, and bulkiness, which are parameters that affect cellular uptake, subcellular distri-bution, and the rate of hydrogen peroxide production. The aim of this thesis was to use a panel of MnPs with different peripheral substituents to investigate how structural modifications that alter the reduction potential, lipophilicity, and size of the MnP affect the cytotoxic and antiproliferative effects in vitro of different MnPs, either alone or in combination with ascorbate, on 2 human breast cancer cell lines which differ in multidrug resistance (PII, MDA-MB-231) and a nontumorigenic human breast cell line (HBL-100). PII and HBL-100 displayed a similar sensitivity to ascorbate-in-duced cytotoxicity while MDA-MB-231 was more resistant. MnP and ascorbate displayed limited cytotoxicity to all cell lines but major cytotoxicity was seen with combinations of 1–5 μMMnTE-2-PyP or MnTE-3-PyP and 1 mMascorbate. The removal of exog-enous MnP or addition of catalase to the medium prevented cyto-toxicity, suggesting that hydrogen peroxide in the extracellular medium is responsible for cytotoxicity. Studies of cellular proliferation (72 h) displayed cytotoxic and cytostatic effects, and find-ings indicated conditions for the potential selectivity for cancer cells (1 μMMnP and 1 mMascorbate). Plasma membrane integrity was lost and cells displayed apoptotic markers after treatment with 5 μMMnTE-2-PyP and 1 mMascorbate (4 h). Immunoblot analy-sis (caspase 7/9, cleaved PARP) suggested caspase-independent cell death. The reduction potential of MnP is the most important parameter for MnP-ascorbate-induced cytotoxicity.