Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation

Abstract

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

“…The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML [216]. Other molecules, such as SRC [217], CHEK1 [218], mTOR [219,220], WEE1 [221], PDK1 [222,223], and MEK [224], have also been chosen as targets together with AURKA in preclinical studies.…”

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

“…For zebrafish xenografts, wild type Tübingen (TU) zebrafish were bred and maintained in the Western Australian Zebrafish Experimental Research Centre (Biomedical Research Facility- Shenton Park, Western Australia). Experiments and data analyses were done as previously described [ 32 ]. Briefly, HPAF-II human pancreatic cancer cells were incubated with Vibrant™-Dil dye (ThermoFisher Scientific) 4 μL/mL in HBSS at 37 °C for 10 min, followed by 15 min on ice in the dark.…”

“…Six to seven-week-old NOD/SCID (NOD.CB17-Prkdcscid/Arc) immune-deficient mice were purchased from the Animal Resources Centre (ARC-Murdoch-Western Australia) and maintained under pathogen-free conditions with water and food provided ad libitum. Mice were injected subcutaneously randomly on either the left or the right flank with 3.5 × 10 6 HPAF-II human pancreatic cancer cells following a previously described protocol [ 32 ]. When tumours reached a volume of about 50 mm 3 (according to the formula: tumour volume = 1/2(length × width 2 ), mice were randomized into two groups and treated with either vehicle (0.5% carboxymethyl cellulose (CMC)/0.4% Tween-80) or JVG045 30 mg/kg as a daily intra-peritoneal injection (IP) in a volume of 250 μL.…”

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

“…For zebra sh xenografts, wild type Tübingen (TU) zebra sh were bred and maintained in the Western Australian Zebra sh Experimental Research Centre (Biomedical Research Facility-Shenton Park, Western Australia). Experiments and data analyses were done as previously described (32). Brie y, HPAF-II human pancreatic cancer cells were incubated with Vibrant™-Dil dye (ThermoFisher Scienti c) 4μL/mL in HBSS at 37°C for 10 minutes, followed by 15 minutes on ice in the dark.…”