Antioxidant pathways and human leukaemia chemotherapeutic sensitivity

Cancer is uncontrolled cellular proliferation devoid of normal biological regulatory mechanisms. Therapeutic treatment of cancers relies on overcoming such proliferation, to allow cytotoxic destruction of cancer cells. Many of the recent therapeutic breakthroughs have been in the targeting of various blood cancers: eg imatinib has effectively eradicated chronic myeloid leukaemia (CML) morbidity. However, acute myeloid leukaemia (AML) remains essentially incurable for the vast majority of patients. The current gold-standard treatment for AML has remained relatively unchanged for decades, consisting of the antimetabolite cytarabine (ara-C) and the anthracycline cytotoxic antibiotic daunorubicin (DNR). The cytoprotective gene haem oxygenase-1 (HO-1) has been found regulated in various forms of cancers (including AML) and implicated in chemotherapeutic drug-resistance. HO-1 protects AML cells from induced apoptosis via its transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2). We show a role for HO-1 in regulating apoptosis in AML cells in response to ara-C and DNR. HO-1 expression was increased in response to both cytotoxic agents. Upon micro RNA (miRNA) silencing of HO-1 expression, both ara-C and DNR stimulated greater apoptotic responses in these silenced AML cells. A concurrent induction in reactive oxygen species (ROS) generation was observed. Studies with ara-C-resistant AML cell lines (THP1araC(1)) showed there to be significantly suppressed levels of Nrf2 and HO-1. A miRNA screen in these resistant cells revealed reduced basal miR-196a expression. One of miR-196a’s targets is the Nrf2-inhibitory protein Bach1 (BTB and CNC homology 1), which was found to be elevated in these cells. Exogenous replacement of miR-196a with the introduction of a miR-mimic, suppressed the Bach1 overexpression, elevated HO-1 expression, and reintroduced sensitivity towards ara-C. These findings suggest HO-1 inhibition in conjunction with chemotherapy would improve the number of cases who reach complete remission (CR).

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2013

Author dc:creator

• Heasman, Sally-Anne

Language dc:language

en