Protein kinase A as target for novel integrated strategies of cancer therapy.
We have studied the role of protein kinase A (PKA) in neoplastic transformation, apoptosis, and angiogenesis and its relationship with other signaling molecules, as a basis for developing novel therapeutic strategies. We demonstrated the involvement of PKA type I (PKA-I) in the transduction of mitogenic signals from different sources and demonstrated functional and structural interactions between PKA-I and the activated epidermal growth factor receptor (EGFR). We contributed to the identification and development of several selective inhibitors of PKA-I, such as 8-Cl-cAMP and a hybrid DNA/RNA antisense oligonucleotide of a novel class (AS-PKA-I) and of EGFR, including mAbC225 and ZD1839 (Iressa). All these agents have been investigated in cancer patients. We demonstrated the therapeutic potential of the combined blockade of PKA-I and EGFR, reporting a synergistic antitumor effect when their inhibitors are used in combination. We have also shown that PKA-I and EGFR inhibitors are able to cooperate with selected class of cytotoxic drugs and with ionizing radiation, causing a synergistic inhibition of tumor growth in vitro and in vivo, accompanied by inhibition of expression of growth and angiogenic factors and by suppression of vessel production. Moreover, PKA-I is implicated in a bcl-2-dependent apoptotic pathway, and we have recently reported a cooperative antitumor and proapoptotic effect of AS-PKA-I in combination with an AS-bcl-2. Finally, we have shown that AS-PKA-I also has antitumor and antiangiogenic effects following oral administration and that they can be greatly enhanced in combination with oral ZD1839 and oral taxanes.
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, 80131 Napoli, Italy. gtortora@unina.it
Giampaolo
G
Tortora
Fortunato
F
Ciardiello
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002455:Cell Division / Q000502:physiology; D003131:Combined Modality Therapy; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic; D015290:Second Messenger Systems / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases