Molecular-targeted therapies have been recently proposed as alternative treatments of cancer. Theeffectiveness of many classical anticancer drugs is in fact limited by their severe side effects andrapid emergence of drug-resistance. Thus, a major challenge is the design of new agents able tointeract with specific cellular components with reduced toxicity at effective doses. The mainmolecular targets for the development of new anticancer drugs include cell surface receptors, signaltransduction pathways, enzymes, gene transcription targets, ubiquitin-proteasome/heat shockproteins, and anti-angiogenesis agents. During the last decade, we have designed and synthesizedseries of compounds capable of interacting with different cellular components, often overexpressedor altered in cancerous cells, namely Apurinic Apirimidinic Endonuclease-1 (APE-1),1poly(ADP-ribose)polymerase-1 (PARP-1), Mn-superoxide dismutase (Mn-SOD),2 MDA-7/IL-24,gp130,3 and topoisomerases.4,5Several nitrogen-containing polycyclic derivatives, showing attractive drug-like properties, wereidentified by computer aided design and demonstrated as promising cytotoxic agents in a panel ofcancer cell lines. The most representative analogs show a peculiar chemical feature consisting of ahydrazine linking a pyrroloquinoxaline to a heteroaroyl system. The cytotoxic profile of thesecompounds has been assessed by in vitro MTT, colony formation, and flow cytometry assays in awide panel of human cancer cell lines. Some of the synthesized compounds showed an interestingprofile at sub-micromolar concentrations. In particular, one of the most active compounds (SC144)has been selected for an in depth biological investigation. An excellent in vivo efficacy wasascertained for such a derivative by studies on xenografted mice, while flow cytometric studiesindicated its capability to arrest cell cycle progression at the G0/G1 phase in several cell lines.Further mechanistic studies revealed that our compound is able to induce reactive oxygen species(ROS) likely due to inhibition of Mn-SOD thus eliciting superoxide-mediated apoptosis throughmitochondrial pathway. SC144 was also showed able to up-regulate MDA-7/IL-24 and cell surfaceboundFas/CD95 expression in colon cancer cells, while Cyclin D1 levels were reduced. Morerecently, the anticancer activity of SC144 was associated with the induction of gp130phosphorylation and deglycosylation and inhibition of the expression of downstream target genes.In addition, the compound showed selective inhibition of gp130 ligand-triggered signaling. Thepotential of SC144 as a drug candidate was supported by either its oral bioavailability in a mousexenograft model of human ovarian cancer, in which it suppressed tumor growth without causingdamage to normal tissues, and its synergistic effect when used in combination with conventionalchemotherapeutic agents.References1 Aiello F.; Shabaik Y.; Esqueda A.; Sanchez T. W.; Grande F.; Garofalo A.; Neamati N. CHEMMEDCHEM,2012, 7, 1825-1839.2Grande F.; Yamada R.; Cao X.; Aiello F., Garofalo A.; Neamati N. Expert Opin. Inv. Drug, 2009, 18, 555-568.3Xu S.; Grande F.; Garofalo A.; Neamati N. Mol. Cancer Ther. (accepted).4Caruso A.; Lancelot J.C.; El-Kashef H.; Sinicropi M.S.; Legay R.; Lesnard A.; Rault S. Tetrahedron, 2009,65, 10400-10405.5Cresteil T.; Rault S.; Aubert G.; Lancelot J.C.; Caruso A.;. Lesnard A. PATENT, FR N°1251491 2012.
Innovative strategies for the development of new anticancer agents
GRANDE, Fedora;AIELLO, Francesca;SINICROPI, Maria Stefania;Garofalo A.
2013-01-01
Abstract
Molecular-targeted therapies have been recently proposed as alternative treatments of cancer. Theeffectiveness of many classical anticancer drugs is in fact limited by their severe side effects andrapid emergence of drug-resistance. Thus, a major challenge is the design of new agents able tointeract with specific cellular components with reduced toxicity at effective doses. The mainmolecular targets for the development of new anticancer drugs include cell surface receptors, signaltransduction pathways, enzymes, gene transcription targets, ubiquitin-proteasome/heat shockproteins, and anti-angiogenesis agents. During the last decade, we have designed and synthesizedseries of compounds capable of interacting with different cellular components, often overexpressedor altered in cancerous cells, namely Apurinic Apirimidinic Endonuclease-1 (APE-1),1poly(ADP-ribose)polymerase-1 (PARP-1), Mn-superoxide dismutase (Mn-SOD),2 MDA-7/IL-24,gp130,3 and topoisomerases.4,5Several nitrogen-containing polycyclic derivatives, showing attractive drug-like properties, wereidentified by computer aided design and demonstrated as promising cytotoxic agents in a panel ofcancer cell lines. The most representative analogs show a peculiar chemical feature consisting of ahydrazine linking a pyrroloquinoxaline to a heteroaroyl system. The cytotoxic profile of thesecompounds has been assessed by in vitro MTT, colony formation, and flow cytometry assays in awide panel of human cancer cell lines. Some of the synthesized compounds showed an interestingprofile at sub-micromolar concentrations. In particular, one of the most active compounds (SC144)has been selected for an in depth biological investigation. An excellent in vivo efficacy wasascertained for such a derivative by studies on xenografted mice, while flow cytometric studiesindicated its capability to arrest cell cycle progression at the G0/G1 phase in several cell lines.Further mechanistic studies revealed that our compound is able to induce reactive oxygen species(ROS) likely due to inhibition of Mn-SOD thus eliciting superoxide-mediated apoptosis throughmitochondrial pathway. SC144 was also showed able to up-regulate MDA-7/IL-24 and cell surfaceboundFas/CD95 expression in colon cancer cells, while Cyclin D1 levels were reduced. Morerecently, the anticancer activity of SC144 was associated with the induction of gp130phosphorylation and deglycosylation and inhibition of the expression of downstream target genes.In addition, the compound showed selective inhibition of gp130 ligand-triggered signaling. Thepotential of SC144 as a drug candidate was supported by either its oral bioavailability in a mousexenograft model of human ovarian cancer, in which it suppressed tumor growth without causingdamage to normal tissues, and its synergistic effect when used in combination with conventionalchemotherapeutic agents.References1 Aiello F.; Shabaik Y.; Esqueda A.; Sanchez T. W.; Grande F.; Garofalo A.; Neamati N. CHEMMEDCHEM,2012, 7, 1825-1839.2Grande F.; Yamada R.; Cao X.; Aiello F., Garofalo A.; Neamati N. Expert Opin. Inv. Drug, 2009, 18, 555-568.3Xu S.; Grande F.; Garofalo A.; Neamati N. Mol. Cancer Ther. (accepted).4Caruso A.; Lancelot J.C.; El-Kashef H.; Sinicropi M.S.; Legay R.; Lesnard A.; Rault S. Tetrahedron, 2009,65, 10400-10405.5Cresteil T.; Rault S.; Aubert G.; Lancelot J.C.; Caruso A.;. Lesnard A. PATENT, FR N°1251491 2012.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
