Signaling Proteins as Innovative Targets for Antineoplastic Therapy: Our Experience with the Signaling Protein C-myc

Cimoli, Guido; Bagnasco, Luca; Pescarolo, Maria Pia; Avignolo, Carlo; Melchiori, A; Pasa, Stefania; Biasotti, Barbara; Taningher, Maurizio; Parodi, Silvio

doi:10.1177/030089160108700636

Cited by 13 publications

(4 citation statements)

References 4 publications

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“…This peptide was able to interfere with c-MYC functions, as induction of cell proliferation and transactivation of ODC at a concentration of 1-10 µM. In a more recent study these authors used a retro-in-verso peptide also corresponding to helix-1 of c-MYC [100,101]: this peptide was 5-10 fold more effective and 30 times more stable in culture medium than the previously used peptide and may therefore be tested in animal studies in the future.…”

Section: Inhibition Of Myc/max Dimerizationmentioning

confidence: 99%

The MYC Oncogene as a Cancer Drug Target

Hermeking

2003

CCDT

123

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The universal deregulation of c-myc gene expression in tumor cells suggests that this oncogene represents an attractive target for cancer therapeutic purposes. The same applies to the N-myc gene, which has a more restricted tissue specificity. Translocation (e.g., c-myc in Burkitt's lymphoma), or amplification (e.g., N-myc in neuroblastoma) of myc genes has been causally linked to tumor formation. Furthermore, the c-myc promoter integrates diverse mitogenic signalling cascades, which are constitutively activated in tumor cells, and translates them into expression of the c-MYC transcription factor, which promotes cell proliferation by regulating the expression of numerous target genes. Recent experimental data suggest, that even a brief inhibition of c-myc expression may be sufficient to permanently stop tumor growth and induce regression of tumors. Attempts to identify specific inhibitors of c-MYC/MAX dimerization have yielded promising results. In addition, downstream-target genes of c-MYC represent attractive targets for tumor therapy. Tumor cells expressing c-MYC at elevated levels are sensitized to treatment with DNA-damaging drugs. In mice and presumably also in human patients, the successful treatment of c-myc-induced tumors with conventional chemotherapy depends on the presence of functional p53. Therefore, restoration of this pathway, which is commonly lost in cancer cells, may enhance therapy of c-myc-induced tumors. These and other recent developments, which address the use of myc genes as therapeutic targets for cancer treatment, are discussed in this review.

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Section: Inhibition Of Myc/max Dimerizationmentioning

confidence: 99%

The MYC Oncogene as a Cancer Drug Target

Hermeking

2003

CCDT

123

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“…In colon cancer, its expression is increased and deregulated after APC inactivation (a "hard" DNA alteration present in more than 70% of colon cancers) (3). In conclusion, c-Myc deregulation has emerged as a central oncogenic switch in many human cancers (4). Which high incidence cancers will be especially "addicted"/hypersensitive to c-Myc inhibitors (perhaps in association with inhibitors of other signaling-proteins) is still unknown.…”

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confidence: 99%

Sequence specific peptidomimetic molecules inhibitors of a protein–protein interaction at the helix 1 level of c‐Myc

et al. 2005

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Our work is focused in the broad area of strategies and efforts to inhibit protein-protein interactions. The possible strategies in this field are definitely much more varied than in the case of ATP-pocket inhibitors. In our previous work (10), we reported that a retro-inverso (RI) form of Helix1 (H1) of c-Myc, linked to an RI-internalization sequence arising from the third alpha-helix of Antennapedia (Int) was endowed with an antiproliferative and proapoptotic activity toward the cancer cell lines MCF-7 and HCT-116. The activity apparently was dependent upon the presence of the Myc motif. In this work, by ala-scan mapping of the H1 portion of our molecules with D-aa, we found two amino acids necessary for antiproliferative activity: D-Lys in 4 and D-Arg in 5 (numbers refer to L-forms). In the natural hetero-dimer, these two side chains project to the outside of the four alpha-helix bundle. Moreover, we were able to obtain three peptides more active than the original lead. They strongly reduced cell proliferation and survival (RI-Int-VV-H1-E2A,S6A,F8A; RI-Int-VV-H1-S6A,F8A,R11A; RI-Int-VV-H1-S6A,F8A,Q13A): after 8 days at 10 muM total cell number was approximately 1% of the number of cells initially seeded. In these more potent molecules, the ablated side chains project to the inside in the corresponding natural four alpha-helix bundle. In the present work, we also investigated the behavior of our molecules at the biochemical level. Using both a circular dichroism (CD) and a fluorescence anisotropy approach, we noted that side chains projecting at the interior of the four alpha-helix bundle are needed for inducing the partial unfolding of Myc-H2, without an opening of the leucine zipper. Side chains projecting at the outside are not required for this biochemical effect. However, antiproliferative activity had the opposite requirements: side chains projecting at the outside of the bundle were essential, and, on the contrary, ablation of one side chain at a time projecting at the inside increased rather than decreased biological activity. We conclude that our active molecules probably interfere at the level of a protein-protein interaction between Myc-Max and a third protein of the transcription complex. Finally, CD and nuclear magnetic resonance (NMR) data, plus dynamic simulations, suggest a prevalent random coil conformation of the H1 portion of our molecules, at least in diluted solutions. The introduction of a kink (substitution with proline in positions 5 or 7) led to an important reduction of biological activity. We have also synthesized a longer peptido-mimetic molecule (RI-Int-H1-S6A,F8A-loop-H2) with the intent of obtaining a wider zone of interaction and a stronger interference at the level of the higher-order structure (enhanceosome). RI-Int-H1-S6A,F8A-loop-H2 was less active rather than more active in respect to RI-Int-VV-H1-S6A,F8A, apparently because it has a clear bent to form a beta-sheet (CD and NMR data).

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“…Fourth, that a combination of chemotherapy agents with different toxicities would allow maximum dosing of each of the component drugs without excessive toxicity. These principles were adapted for cancer management more than 50 years ago as a result of successful screening with sensitive bacteria to antibacterial drugs [14, 15]. Unfortunately, we have learned that cancer is far more complex than bacteria.…”

Section: Standard Treatment For Advanced Cancermentioning

confidence: 99%

Personalized Cancer Approach: Using RNA Interference Technology

et al. 2011

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Normal cellular survival is dependent on the cooperative expression of genes' signaling through a broad array of DNA patterns. Cancer, however, has an Achilles' heel. Its altered cellular survival is dependent on a limited subset of signals through mutated DNA, possibly as few as three. Identification and control of these signals through the use of RNA interference (RNAi) technology may provide a unique clinical opportunity for the management of cancer that employs genomic-proteomic profiling to provide a molecular characterization of the cancer, leading to targeted therapy customized to an individual cancer signal. Such an approach has been described as "personalized therapy." The present review identifies unique developing technology that employs RNAi as a method to target, and therefore block, signaling from mutated DNA and describes a clinical pathway toward its development in cancer therapy.

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Signaling Proteins as Innovative Targets for Antineoplastic Therapy: Our Experience with the Signaling Protein C-myc

Cited by 13 publications

References 4 publications

The MYC Oncogene as a Cancer Drug Target

The MYC Oncogene as a Cancer Drug Target

Sequence specific peptidomimetic molecules inhibitors of a protein–protein interaction at the helix 1 level of c‐Myc

Personalized Cancer Approach: Using RNA Interference Technology

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