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Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.

Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A, Tralau-Stewart C, Capece D, D'Andrea D, Bua M, Boyle E, van Duin M, Zoppoli P, Jaxa-Chamiec A, Thotakura AK, Dyson J, Walker BA, Leonardi A, Chambery A, Driessen C, Sonneveld P, Morgan G, Palumbo A, Tramontano A, Rahemtulla A, Ruvo M, Franzoso G - Cancer Cell (2014)

Bottom Line: Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells.Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.

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Schematic Representation of the Therapeutic GADD45β/MKK7-Targeting Strategy in CancerDepicted is the crosstalk between the NF-κB and JNK pathways promoting the survival of cancer cells and cells exposed to inflammatory stimuli. Also illustrated is the NF-κB-dependent, Gadd45β/MKK7-mediated mechanism suppressing apoptotic JNK signaling in MM cells. Our therapeutic strategy to block the NF-κB survival function in a cancer-selective manner with DTP3 (green) is compared with conventional therapeutic approaches (e.g., IKKβ and proteasome inhibitors; red) also aimed at inhibiting the NF-κB pathway in cancer. MAP3Ks, mitogen-activated protein kinase kinase kinases; ROS, reactive oxygen species.
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fig8: Schematic Representation of the Therapeutic GADD45β/MKK7-Targeting Strategy in CancerDepicted is the crosstalk between the NF-κB and JNK pathways promoting the survival of cancer cells and cells exposed to inflammatory stimuli. Also illustrated is the NF-κB-dependent, Gadd45β/MKK7-mediated mechanism suppressing apoptotic JNK signaling in MM cells. Our therapeutic strategy to block the NF-κB survival function in a cancer-selective manner with DTP3 (green) is compared with conventional therapeutic approaches (e.g., IKKβ and proteasome inhibitors; red) also aimed at inhibiting the NF-κB pathway in cancer. MAP3Ks, mitogen-activated protein kinase kinase kinases; ROS, reactive oxygen species.

Mentions: Importantly, DTP3 retained potent anticancer activity in an orthotopic xenograft model of MM, which more faithfully recapitulates the human disease. All the control mice developed severe limb paralysis and died within 32 days of treatment start, resulting in a median OS of 26 days (Figure 7F). Strikingly, DTP3 administration over a period of 8 weeks, at a dose of 29 mg/kg/day, extended the median OS of the mice past the experimental end point on day 161, without producing any apparent side effect, thus demonstrating the potent therapeutic efficacy of DTP3 against MM, in vivo, and the excellent tolerability of this agent at doses that achieve full therapeutic efficacy. Collectively, together with the data in primary MM cells (Figures 6A–6D; Figures S6A and S6B), these results underscore the potency, safety, and cancer cell specificity of the pharmacological approach targeting the GADD45β/MKK7 complex in MM and identify DTP3 as a therapeutic selectively inhibiting the NF-κB survival pathway in cancer (Figure 8).


Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.

Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A, Tralau-Stewart C, Capece D, D'Andrea D, Bua M, Boyle E, van Duin M, Zoppoli P, Jaxa-Chamiec A, Thotakura AK, Dyson J, Walker BA, Leonardi A, Chambery A, Driessen C, Sonneveld P, Morgan G, Palumbo A, Tramontano A, Rahemtulla A, Ruvo M, Franzoso G - Cancer Cell (2014)

Schematic Representation of the Therapeutic GADD45β/MKK7-Targeting Strategy in CancerDepicted is the crosstalk between the NF-κB and JNK pathways promoting the survival of cancer cells and cells exposed to inflammatory stimuli. Also illustrated is the NF-κB-dependent, Gadd45β/MKK7-mediated mechanism suppressing apoptotic JNK signaling in MM cells. Our therapeutic strategy to block the NF-κB survival function in a cancer-selective manner with DTP3 (green) is compared with conventional therapeutic approaches (e.g., IKKβ and proteasome inhibitors; red) also aimed at inhibiting the NF-κB pathway in cancer. MAP3Ks, mitogen-activated protein kinase kinase kinases; ROS, reactive oxygen species.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4197335&req=5

fig8: Schematic Representation of the Therapeutic GADD45β/MKK7-Targeting Strategy in CancerDepicted is the crosstalk between the NF-κB and JNK pathways promoting the survival of cancer cells and cells exposed to inflammatory stimuli. Also illustrated is the NF-κB-dependent, Gadd45β/MKK7-mediated mechanism suppressing apoptotic JNK signaling in MM cells. Our therapeutic strategy to block the NF-κB survival function in a cancer-selective manner with DTP3 (green) is compared with conventional therapeutic approaches (e.g., IKKβ and proteasome inhibitors; red) also aimed at inhibiting the NF-κB pathway in cancer. MAP3Ks, mitogen-activated protein kinase kinase kinases; ROS, reactive oxygen species.
Mentions: Importantly, DTP3 retained potent anticancer activity in an orthotopic xenograft model of MM, which more faithfully recapitulates the human disease. All the control mice developed severe limb paralysis and died within 32 days of treatment start, resulting in a median OS of 26 days (Figure 7F). Strikingly, DTP3 administration over a period of 8 weeks, at a dose of 29 mg/kg/day, extended the median OS of the mice past the experimental end point on day 161, without producing any apparent side effect, thus demonstrating the potent therapeutic efficacy of DTP3 against MM, in vivo, and the excellent tolerability of this agent at doses that achieve full therapeutic efficacy. Collectively, together with the data in primary MM cells (Figures 6A–6D; Figures S6A and S6B), these results underscore the potency, safety, and cancer cell specificity of the pharmacological approach targeting the GADD45β/MKK7 complex in MM and identify DTP3 as a therapeutic selectively inhibiting the NF-κB survival pathway in cancer (Figure 8).

Bottom Line: Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells.Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.

Show MeSH
Related in: MedlinePlus