cardiotoxicity, CaMKII, stem cells

A number of anti-cancer drugs in development or on the market are now recognised to have adverse effects on the heart, leading to patient mortality via cardiotoxicity. Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is recognised as a key regulator of myocardial function with a particularly prominent role in pathophysiological conditions where stiffening and contractile dysfunction of the heart occurs. We have already performed in vivo experiments that have highlighted CaMKIIδ as a potential cardiac target for the anti-cancer drugs imatinib and sunitinib. Both drugs lead to an increased expression and activation of CaMKIIδ in the heart following acute and chronic treatment and this coincides with reduced cardiac performance¹.  Elevated CaMKII levels are well known to contribute to cardiovascular disease with increased CaMKII expression and activation being widely recognised as a marker of cardiac dysfunction. Further work is now required to confirm our finding and to explore (i) the exact mechanisms of action these anti-cancer drugs use to exert their effects on the heart at a cellular level and (ii) whether interventions, known to promote cardiovascular health, might reduce or reverse the cardiotoxic effects at a cellular level.  Omega 3 EPA is known to be beneficial for cardiovascular health and to possess anti-inflammatory properties. Little is known of whether treatment with omega 3 fatty acids might be cardioprotective against the toxic effects of anti-cancer drugs however there is some evidence in the literature to suggest this could be an area worthy of investigation².

Hypothesis: CaMKIIδ activation is a key modulator of the cardiotoxic effects of imatinib and sunitinib and this can be reversed following treatment with omega-3 fatty acids.

Aims and Objectives: Recent evidence in rats has suggested that in vivo administration of fish omega 3 fatty acids significantly reduces the oxidative stress accompanying doxorubicin treatment of these animals³. However, nothing is known of the cellular mechanisms that (a) lead to the cardiotoxic effects and (b) that could be responsible for reversing pathological events. These will form the key objectives of this proposal.

Thermal shift assay⁴ and Western blotting

CaMKII phosphorylation and oxidation changes in iPSC cardiomyocytes using specific antibodies

In-house kinase assay

Viability and proliferation assays

Assess phenotypic alterations and hyperproliferation in adult cardiac fibroblasts ⁵. 

Assays to measure omega-3 fatty acids to assess reduction/reversal of the pathological effects.  

1. Mooney L. et al (2015) Br.J.Pharmacol.172, 4342-4354, 2. Kakoti et al (2015) Front. Cardiovasc. Med. 2: 38: 1-6   3. Uygur R. et al (2014) Hum.Exp.Toxicol. 33, 435-445.  4. Jafari R. et al (2014) Nature Protocols 9, 2100-2122, 5. Martin T. et al (2014) Pflugers Arch. 466, 319-330