Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors)
Introduction
Every year around 600,000 people on this planet die of pancreatic cancers. The collective median survival time of all pancreatic cancer patients is 4–6 months. The overall 5-year survival rate for this disease is less than 5%. The main reason for such a poor survival rate is that so far no clinically effective therapeutic has been developed for this disease. Around 30% of all human cancers carry oncogenic RAS mutations, and most notably more than 90% of human pancreatic cancers are associated with such mutations, in particular K-RAS at codon 12 [1], which causes the constitutive activation of the G protein RAS, eventually leading to the abnormal activation of PAK1, a Rac/CDC42-dependent Ser/Thr kinase, or another Ser/Thr kinase called AKT/PKB, through the PI-3 kinase cascade [2], [3]. An anti-biotic called kigamicin D, which blocks the PI-3 kinase/AKT pathway, strongly suppresses the growth of human pancreatic cancer xenografts in mice, suggesting that this pathway might be one of the selective targets for anti-pancreatic cancer drugs [3].
FK228, the most potent histone deacetylase (HDAC) inhibitor so far discovered, has been shown to suppress the growth of both v-Ha-RAS-induced sarcoma allograft [4], and human pancreatic cancer cell lines such as Capan-1 in cell culture (IC50: 3 nM) which carry both K-RAS and p53 mutants [5]. Furthermore, we and others found that (i) PAK1 is essential for RAS-transformation [2], [6], that (ii) the growth of RAS-induced sarcoma allograft in mice is almost completely suppressed by a combination of two complementary Tyr-kinase inhibitors, PP1 and AG 879, which block PAK1 activation by inhibiting a Src family kinase(s) and ETK, respectively [2], [7], [8], with their IC50 around 10 nM, and that (iii) FK228 blocks the activation of PAK1 in RAS transformants and estrogen-dependent breast cancer cells [9]. Based on these previous observations, we have examined the therapeutic potential of FK228 alone, a combination of PP1 with either AG 879 or its water-soluble derivative called GL-2003 on the growth of Capan-1 xenograft in mice.
Section snippets
Materials
FK228 was supplied from Astellas Pharma (former Fujisawa Pharmaceuticals) as previously described [10]. PP1 and AG 879 were synthesized as previously [2]. GL-2003, a water-soluble derivative of AG 879, was synthesized via GL-2002 [8], and the detail of their synthesis will be described in Appendix A1 (supplement information). In brief, as shown in Fig. 1, GL-2002 (compound 4) was deprotected with SnCl4 in AcOEt, yielding GL-2003 (compound 5).
The human pancreatic cancer cell line Capan-1 and
PP1 and GL-2003 cause a synergetic effect in the therapy of human pancreatic cancer xenograft in mice
For the combination therapy of PP1 and AG 879, we followed the exact dose (20 mg/kg of each, i.p. twice a week) as we used previously for testing on RAS-induced sarcoma allograft in mice [2]. For FK228 therapy, we chose a mean dose (1.5 mg/kg, i.p. twice a week), between 1 mg/kg for breast cancers xenografts and 2.5 mg/kg for NF xenograft in mice [10], [12]. As shown in Fig. 2, both FK228 alone or the PP1/AG 879 combination showed the almost same anti-cancer potential, that is around 50% inhibition
Acknowledgements
We are grateful to Dr Hidenori Nakajima of Astellas Pharma for his generous gift of FK228 as the positive control, Ms Maureen Nerrie for her soft agar assay, and Prof. Tony Burgess for his continued support. This work was supported in part by the Denise Terrill Classic Award from Texas NF Foundation.
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