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Lipid peroxidation product 4-hydroxynonenal as factor of oxidative homeostasis supporting bone regeneration with bioactive glasses

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Mrakovcic L., Wildburger R., Jaganjac M., Cindric M., Cipak A., Borovic-Sunjic S., Waeg G., Milankovic A. M., Zarkovic N.

Acta Biochimica Polonica

2010

vol. 57

issue 2

173-178

Bone regeneration is a process of vital importance since fractures of long bones and large joints have a highly deleterious impact on both, individuals and society. Numerous attempts have been undertaken to alleviate this severe medical and social problem by development of novel bioactive materials, among which bioactive glass is the most attractive because of its osteoconductive and osteostimulative properties. Since lipid peroxidation is an important component of systematic stress response in patients with traumatic brain injuries and bone fractures, studies have been undertaken of the molecular mechanisms of the involvement of 4-hydroxynonenal (HNE), an end product of lipid peroxidation, in cellular growth regulation. We found that HNE generated in bone cells grown in vitro on the surfaces of bioactive glasses 45S5 and 13-93. This raises an interesting possibility of combined action of HNE and ionic bioglass dissolution products in enhanced osteogenesis probably through a mitogen-activated protein kinase (MAPK) pathway. While the proposed mechanism still has to be elucidated, the finding of HNE generation on bioglass offers a new interpretation of the osteoinducting mechanisms of bioglass and suggests the possibility of tissue engineering based on manipulations of oxidative homeostasis.

Growth suppression of human breast carcinoma stem cells by lipid peroxidation product 4-hydroxy-2-nonenal and hydroxyl radical-modified collagen

81%

Cipak A., Mrakovcic L., Ciz M., Lojek A., Mihaylova B., Goshev I., Jaganjac M., Cindric M., Sitic S., Margaritoni M., Waeg G., Balic M., Zarkovic N.

Acta Biochimica Polonica

2010

vol. 57

issue 2

165-171

Breast cancer is a leading cause of mortality and morbidity in women, mostly due to high metastatic capacity of mammary carcinoma cells. It has been revealed recently that metastases of breast cancer comprise a fraction of specific stem-like cells, denoted as cancer stem cells (CSCs). Breast CSCs, expressing specific surface markers CD44+CD24-/lowESA+ usually disseminate in the bone marrow, being able to spread further and cause late metastases. The fundamental factor influencing the growth of CSCs is the microenvironment, especially the interaction of CSCs with extracellular matrix (ECM). The structure and function of ECM proteins, such as the dominating ECM protein collagen, is influenced not only by cancer cells but also by various cancer treatments. Since surgery, radio and chemotherapy are associated with oxidative stress we analyzed the growth of breast cancer CD44+CD24-/lowESA+ cell line SUM159 cultured on collagen matrix in vitro, using either native collagen or the one modified by hydroxyl radical. While native collagen supported the growth of CSCs, oxidatively modified one was not supportive. The SUM159 cell cultures were further exposed to a supraphysiological (35 µM) dose of the major bioactive lipid peroxidation product 4-hydroxynonenal (HNE), a well known as 'second messenger of free radicals', which has a strong affinity to bind to proteins and acts as a cytotoxic or as growth regulating signaling molecule. Native collagen, but not oxidised, abolished cytotoxicity of HNE, while oxidized collagen did not reduce cytotoxicity of HNE at all. These preliminary findings indicate that beside direct cytotoxic effects of anticancer therapies consequential oxidative stress and lipid peroxidation modify the microenvironment of CSCs influencing oxidative homeostasis that could additionally act against cancer.

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2 Acta Biochimica Polonica

2 2010

2 Cindric M.

2 Cipak A.

2 Jaganjac M.

2 Mrakovcic L.

2 Waeg G.

2 Zarkovic N.

1 Balic M.

1 Borovic-Sunjic S.

1 Ciz M.

1 Goshev I.

1 Lojek A.

1 Margaritoni M.

1 Mihaylova B.

1 Milankovic A. M.

1 Sitic S.

1 Wildburger R.

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Lipid peroxidation product 4-hydroxynonenal as factor of oxidative homeostasis supporting bone regeneration with bioactive glasses

Growth suppression of human breast carcinoma stem cells by lipid peroxidation product 4-hydroxy-2-nonenal and hydroxyl radical-modified collagen