AbstractSunitinib is a potent multiple tyrosine kinase receptor inhibitor which possesses powerful anti-cancer properties. However, adverse cardiovascular events have been reported in treated patients.
Mitogen activated protein kinase (MAPK) signalling cascades play significant roles in the development of cardiac hypertrophy in response to external stresses. Interestingly, Sunitinib has been shown to produce an inhibitory effect on MAPK signalling. The stress signalling protein mitogen activated kinase kinase 7 (MKK7) is an elective upstream regulator of the c-Jun N-terminal kinase (JNK) pathway and is downstream to apoptosis signalling kinase 1 (ASK1). Specific deletion of MKK7, JNK and ASK1 in hearts has been shown to increase the sensitivity of cardiomyocytes to external stresses.
This thesis investigates Sunitinib-induced cardiotoxicity in 3 month, 12 month and 24 month old male Sprague-Dawley rats. Then, tests the involvement of the ASK1/MKK7/JNK and the protein kinase C α (PKCα) pathways in Sunitinib‐induced cardiotoxicity in 3 month ages rats. The evaluation of potential cardioprotective compounds: NQDI-1 and 2Cl-IB-MECA were also investigated. Changes in cardiac injury specific microRNAs (miRNAs): miR-1, miR-27a, miR-133a and miR-133b levels and cancer specific miRNAs: miR-15a, miR-16-1 and miR-155 were measured in response to Sunitinib and cardioprotective adjunct therapy in both left ventricular tissue and the HL60 cell line.
Sunitinib produced a detrimental effect on haemodynamic function and significantly increased infarct size in all age groups tested. However, in the 24 month and 12 month groups the increase in infarct size was not as pronounced as in the 3 month group. Also, haemodynamic dysfunction was present in all age groups, however, the level of dysfunction varied between the age groups tested. Ageing also demonstrated opposing expression patterns of cardiac injury specific miRNAs and MKK7 phosphorylation levels.
The adjunct therapy NQDI-1 partially attenuated Sunitinib-induced cardiotoxicity by facilitating a reduction in infarct size. However, NQDI-1 did not attenuate Sunitinib-induced declines in haemodynamic function. Interestingly, NQDI-1 attenuated Sunitinib’s inhibition of ASK1/MKK7/JNK pathway and enhanced the anti-cancer properties of Sunitinib in HL60 cells.
The adjunct therapy IB-MECA abrogated both increases in infarct size and the declines in left ventricular developed pressure produced by Sunitinib treatment. However, the decline in heart rate was not attenuated by IB-MECA. IB-MECA attenuated Sunitinib’s inhibition of MKK7 and JNK phosphorylation and the increase in PKCα phosphorylation in left ventricular tissue. Furthermore, IB-MECA did not jeopardise Sunitinib’s anti-cancer properties.
In conclusion, data from this thesis demonstrated that Sunitinib caused cardiotoxicity in all age groups. Also, data highlighted the complexity of cellular signalling mechanisms produced by Sunitinib-induced cardiotoxicity. Inhibition of the ASK1/MKK7/JNK pathway and activation of PKC could be involved in Sunitinib-induced cardiotoxicity. However, the MKK7 signalling was altered by ageing. The use of miRNAs as markers for Sunitinib-induced cardiac injury and anti-cancer capabilities were inconclusive. However, both NQDI-1 and IB¬MECA possess promising cardioprotective properties and did not diminish the anti-cancer properties of Sunitinib in HL60 cells.
|Date of Award||Mar 2018|
|Supervisor||Hardip Sandhu (Supervisor), Helen Maddock (Supervisor), Afthab Hussain (Supervisor) & Christopher Mee (Supervisor)|