KP1339 is a promising
ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of
KP1339 on the in vitro and in vivo activity of the multi-
kinase inhibitor
sorafenib, the current standard first-line
therapy for advanced
hepatoma. Anticancer activity of the parental compounds as compared to the
drug combination was tested against a panel of
cancer cell lines with a focus on
hepatoma. Combination of
KP1339 with
sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both
sorafenib-resistant as well as
sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly,
sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the
ruthenium drug. In addition,
sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent
DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the
KP1339/
sorafenib combination was evaluated in the Hep3B
hepatoma xenograft.
KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to
sorafenib, which induced a 1.9-fold prolonged survival. The combined
therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1
melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of
KP1339 with
sorafenib displays promising activity in vitro and in vivo especially against human
hepatoma models.