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Photoactive CO-releasing complexes containing iron - genotoxicity and ability in HO-1 gene induction in HL-60 cells.

ABSTRACT: This paper presents the results of research on the biological properties of two photoactive CO-releasing molecules containing iron, i.e. (?5-C5H5)Fe(CO)2(?1-N-maleimidato) (complex A) and (?5-C5H5)Fe(CO)2(?1-N-succinimidato) (complex B). We studied their cytotoxicity, genotoxicity and the ability of inducing the HO-1 gene in HL-60 cells. We also investigated the kinetics of DNA damage repair induced by complexes A and B. We demonstrated that complex B was not toxic to HL-60 cells in high doses (above 100 ?M). The ability to induce DNA damage was higher for complex A. Importantly, there was no difference in irradiated and non-irradiated cells for both complexes. DNA damage induced by complex B was repaired efficiently, while the repair of DNA damage induced by complex A was disturbed. Complex B had a minor effect on HO-1 gene expression (less than 2-fold induction), while complex A had induced HO-1 gene expression to a great extent (over 17-fold for 10 ?M) - similarly in irradiated and non-irradiated HL-60 cells. The results of our research indicate that the ability of both complexes to damage DNA and to upregulate HO-1 gene expression is not related to the release of CO. Further research is needed to test whether these compounds can be considered as potential CO carriers in humans.

SUBMITTER: Wysokinski D

PROVIDER: S-EPMC6621133 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Photoactive CO-releasing complexes containing iron - genotoxicity and ability in HO-1 gene induction in HL-60 cells.

Wysokiński Daniel D Lewandowska Patrycja P Zątak Daria D Juszczak Michał M Kluska Magdalena M Lizińska Daria D Rudolf Bogna B Woźniak Katarzyna K

Toxicology research 20190522 4

This paper presents the results of research on the biological properties of two photoactive CO-releasing molecules containing iron, i.e. (η5-C5H5)Fe(CO)2(η1-N-maleimidato) (complex A) and (η5-C5H5)Fe(CO)2(η1-N-succinimidato) (complex B). We studied their cytotoxicity, genotoxicity and the ability of inducing the HO-1 gene in HL-60 cells. We also investi ...[more]

PMID: 31367337

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Project description:Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

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Photoactive CO-releasing complexes containing iron - genotoxicity and ability in HO-1 gene induction in HL-60 cells.

Publications

Photoactive CO-releasing complexes containing iron - genotoxicity and ability in HO-1 gene induction in HL-60 cells.

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