Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A

Abstract

ABSTRACT

Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A

“…PKA may play a role in the transduction of taxol-related bcl-2 phosphorylation and induction of apoptosis (Srivastava et al, 1998). This correlates with our previous demonstration that MBOs targeting PKAI synergize in vitro and cooperate in vivo with taxanes (Tortora et al, 1997(Tortora et al, , 1999. To evaluate the effect of the blockade of PKAI-dependent signal transduction on the sensitivity of the MCF-10A transformed cells to taxanes, we treated these cells with taxol or taxotere in combination with the PKAI antisense MBO.…”

“…Inhibition of PKAI by antisense oligonucleotides targeting its RI␣ regulatory subunit results in cancer cell growth inhibition (Yokozaki et al, 1993). We have shown that a series of antisense oligonucleotides of second generation with mixed backbone structure (mixed backbone oligonucleotides, MBOs) targeting RI␣ can inhibit human cancer cell growth and have a cooperative antitumor effect when combined with selected cytotoxic drugs (Tortora et al, 1997;Tortora et al, 1999). On the other hand, we have previously shown that downregulation of PKAI by different pharmacologic tools, such as cAMP analogues, inhibits c-Ha-ras and c-erbB-2 expression in c-Ha-ras and c-erbB-2 transformed MCF-10A cells, suggesting that PKAI may play a role in c-erbB-2 signaling (Ciardiello et al, 1993).…”

Cyclic adenosine 3′,5′-monophosphate-elevating agents inhibit transforming growth factor-β-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism

“…Similarly, PKA inhibitors may also be considered as therapeutic agents for cancer therapy, as it has been shown that combined blockade of PKA and EGF receptor activities exerts a synergistic antitumor effect in a variety of experimental models both in vitro and in vivo (Tortora and Ciardiello, 2002). Moreover, PKA inhibitors cooperate with cytotoxic drugs and ionizing radiations to inhibit tumor growth and angiogenesis (Tortora et al, 1997;Bianco et al, 2000).…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…The specificity of these inhibitors, however, is questioned (Murray 2008). A more specific approach for PKA manipulation, antisense oligonucleotide-based knockdown of PKA R subunit, has shown anticancer effects in preclinical (Tortora et al 1997) and clinical studies (Goel et al 2006). It remains unknown if these strategies have any effect on glucose control in animal models or human patients with T2D; and (3) disruption of AKAP signaling complexes.…”