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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: Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM.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.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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DTP3 Exhibits Potent Therapeutic Activity against MM, In Vivo, in the Absence of Any Apparent Side Effects(A) Pharmacokinetic (PK) values of DTP3 after single intravenous injection at the dose of 10 mg/kg. AUC, area under the plasma concentration versus time curve; CL, plasma clearance; t1/2, terminal half-life; Vd, volume of distribution. Values denote means ± SD (n = 3).(B) Volumes of subcutaneous U266 myeloma xenografts in mice treated by continual infusion with DTP3 at a dose of 14.5 mg/kg/day or PBS for the times shown. Values denote means ± SEM (n = 16). ∗∗∗p < 0.001.(C) Images of representative myeloma-bearing mice (top) and isolated tumors (bottom) from (B) at day 28.(D) Images of TUNEL assays showing apoptotic cells in representative tumors from (B). Scale bars represent 10 μM. Green, TUNEL; blue, DAPI.(E) Western blots showing total and phosphorylated (P) JNK, and the unprocessed (filled arrowheads) and cleaved (open arrowheads) forms of caspase-3 and its proteolytic substrate, PARP-1, in representative tumors from (B).(F) Percentage survival of mice bearing medullary KMS-12 MM xenografts and treated intermittently by infusion with DTP3 at a dose of 29.0 mg/kg/day or PBS (left; n = 8, each group) for 8 weeks. Also shown is the median OS of each animal cohort (right). ∗∗∗p < 0.0001.See also Figure S7 and Table S6.
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fig7: DTP3 Exhibits Potent Therapeutic Activity against MM, In Vivo, in the Absence of Any Apparent Side Effects(A) Pharmacokinetic (PK) values of DTP3 after single intravenous injection at the dose of 10 mg/kg. AUC, area under the plasma concentration versus time curve; CL, plasma clearance; t1/2, terminal half-life; Vd, volume of distribution. Values denote means ± SD (n = 3).(B) Volumes of subcutaneous U266 myeloma xenografts in mice treated by continual infusion with DTP3 at a dose of 14.5 mg/kg/day or PBS for the times shown. Values denote means ± SEM (n = 16). ∗∗∗p < 0.001.(C) Images of representative myeloma-bearing mice (top) and isolated tumors (bottom) from (B) at day 28.(D) Images of TUNEL assays showing apoptotic cells in representative tumors from (B). Scale bars represent 10 μM. Green, TUNEL; blue, DAPI.(E) Western blots showing total and phosphorylated (P) JNK, and the unprocessed (filled arrowheads) and cleaved (open arrowheads) forms of caspase-3 and its proteolytic substrate, PARP-1, in representative tumors from (B).(F) Percentage survival of mice bearing medullary KMS-12 MM xenografts and treated intermittently by infusion with DTP3 at a dose of 29.0 mg/kg/day or PBS (left; n = 8, each group) for 8 weeks. Also shown is the median OS of each animal cohort (right). ∗∗∗p < 0.0001.See also Figure S7 and Table S6.

Mentions: DTP3 showed high aqueous solubility and very high stability in human serum, owing to its resistance to proteolysis, with a good pharmacokinetic profile and excellent in vivo tolerability, suitable for a therapeutic purpose (Figure 7A; Figure S5D and Table S6).


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)

DTP3 Exhibits Potent Therapeutic Activity against MM, In Vivo, in the Absence of Any Apparent Side Effects(A) Pharmacokinetic (PK) values of DTP3 after single intravenous injection at the dose of 10 mg/kg. AUC, area under the plasma concentration versus time curve; CL, plasma clearance; t1/2, terminal half-life; Vd, volume of distribution. Values denote means ± SD (n = 3).(B) Volumes of subcutaneous U266 myeloma xenografts in mice treated by continual infusion with DTP3 at a dose of 14.5 mg/kg/day or PBS for the times shown. Values denote means ± SEM (n = 16). ∗∗∗p < 0.001.(C) Images of representative myeloma-bearing mice (top) and isolated tumors (bottom) from (B) at day 28.(D) Images of TUNEL assays showing apoptotic cells in representative tumors from (B). Scale bars represent 10 μM. Green, TUNEL; blue, DAPI.(E) Western blots showing total and phosphorylated (P) JNK, and the unprocessed (filled arrowheads) and cleaved (open arrowheads) forms of caspase-3 and its proteolytic substrate, PARP-1, in representative tumors from (B).(F) Percentage survival of mice bearing medullary KMS-12 MM xenografts and treated intermittently by infusion with DTP3 at a dose of 29.0 mg/kg/day or PBS (left; n = 8, each group) for 8 weeks. Also shown is the median OS of each animal cohort (right). ∗∗∗p < 0.0001.See also Figure S7 and Table S6.
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fig7: DTP3 Exhibits Potent Therapeutic Activity against MM, In Vivo, in the Absence of Any Apparent Side Effects(A) Pharmacokinetic (PK) values of DTP3 after single intravenous injection at the dose of 10 mg/kg. AUC, area under the plasma concentration versus time curve; CL, plasma clearance; t1/2, terminal half-life; Vd, volume of distribution. Values denote means ± SD (n = 3).(B) Volumes of subcutaneous U266 myeloma xenografts in mice treated by continual infusion with DTP3 at a dose of 14.5 mg/kg/day or PBS for the times shown. Values denote means ± SEM (n = 16). ∗∗∗p < 0.001.(C) Images of representative myeloma-bearing mice (top) and isolated tumors (bottom) from (B) at day 28.(D) Images of TUNEL assays showing apoptotic cells in representative tumors from (B). Scale bars represent 10 μM. Green, TUNEL; blue, DAPI.(E) Western blots showing total and phosphorylated (P) JNK, and the unprocessed (filled arrowheads) and cleaved (open arrowheads) forms of caspase-3 and its proteolytic substrate, PARP-1, in representative tumors from (B).(F) Percentage survival of mice bearing medullary KMS-12 MM xenografts and treated intermittently by infusion with DTP3 at a dose of 29.0 mg/kg/day or PBS (left; n = 8, each group) for 8 weeks. Also shown is the median OS of each animal cohort (right). ∗∗∗p < 0.0001.See also Figure S7 and Table S6.
Mentions: DTP3 showed high aqueous solubility and very high stability in human serum, owing to its resistance to proteolysis, with a good pharmacokinetic profile and excellent in vivo tolerability, suitable for a therapeutic purpose (Figure 7A; Figure S5D and Table S6).

Bottom Line: Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM.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.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