TY - JOUR
T1 - The leader peptide of a human rec. MnSOD as molecular carrier which delivers high amounts of cisplatin into tumor cells inducing a fast apoptosis in vitro
AU - Borrelli, Antonella
AU - Schiattarella, Antonietta
AU - Mancini, Roberto
AU - Morelli, Franco
AU - Capasso, Clemente
AU - De Luca, Viviana
AU - Gori, Enrico
AU - Mancini, Aldo
PY - 2011/1/15
Y1 - 2011/1/15
N2 - The leader peptide of a recombinant MnSOD (rMnSOD-Lp) constitutes the carrier that allows rMnSOD to penetrate tumor cells. A synthetic preparation of rMnSOD-Lp was 68Ga labeled (rMnSOD-Lp-68Ga) and injected into animals bearing spontaneous mammary cancers, followed by PET examinations, which demonstrated unambiguously the tumor sites in all the animals, suggesting that if rMnSOD-Lp was able to transport the radioisotope into tumor cells, it would also be able to deliver cytotoxic molecules. The rMnSOD-Lp was, therefore, conjugated to cisplatin (rMnSOD-Lp-CC) and added to cultured tumor cells. Equal concentrations of cisplatin were used for the tests. After treating the ovarian cancer cells with 11.1 μg of cisplatin alone, analysis by atomic absorbance spectrophotometry was able to detect only 6 ng of platinum, whereas when the same cells were treated with the same amount of cisplatin conjugated to leader peptide rMnSOD, 387 ng of platinum were detected, i.e., an amount 80 times greater. Only the tumor cells died following treatment with rMnSOD-Lp-CC; molecular analysis revealed that its addition generated an increasing expression of Erk-2 and Bax products, which could be inhibited only by a selective MAP/ERK kinase inhibitor (PD98059), revealing that rMnSOD-Lp-CC has an apoptotic function, exactly as occurs when using the cisplatin alone. Data are statistically significant and indicate that by using rMnSOD-Lp-CC, the cisplatin can be transformed from an agent with antireplicative activity into a specific and selective antitumor molecule, increasing its therapeutic index. We think that rMnSOD-Lp-CC deserves to be considered as a new antitumor agent.
AB - The leader peptide of a recombinant MnSOD (rMnSOD-Lp) constitutes the carrier that allows rMnSOD to penetrate tumor cells. A synthetic preparation of rMnSOD-Lp was 68Ga labeled (rMnSOD-Lp-68Ga) and injected into animals bearing spontaneous mammary cancers, followed by PET examinations, which demonstrated unambiguously the tumor sites in all the animals, suggesting that if rMnSOD-Lp was able to transport the radioisotope into tumor cells, it would also be able to deliver cytotoxic molecules. The rMnSOD-Lp was, therefore, conjugated to cisplatin (rMnSOD-Lp-CC) and added to cultured tumor cells. Equal concentrations of cisplatin were used for the tests. After treating the ovarian cancer cells with 11.1 μg of cisplatin alone, analysis by atomic absorbance spectrophotometry was able to detect only 6 ng of platinum, whereas when the same cells were treated with the same amount of cisplatin conjugated to leader peptide rMnSOD, 387 ng of platinum were detected, i.e., an amount 80 times greater. Only the tumor cells died following treatment with rMnSOD-Lp-CC; molecular analysis revealed that its addition generated an increasing expression of Erk-2 and Bax products, which could be inhibited only by a selective MAP/ERK kinase inhibitor (PD98059), revealing that rMnSOD-Lp-CC has an apoptotic function, exactly as occurs when using the cisplatin alone. Data are statistically significant and indicate that by using rMnSOD-Lp-CC, the cisplatin can be transformed from an agent with antireplicative activity into a specific and selective antitumor molecule, increasing its therapeutic index. We think that rMnSOD-Lp-CC deserves to be considered as a new antitumor agent.
KW - cisplatin
KW - leader peptide
KW - molecular carrier
KW - rMnSOD
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U2 - 10.1002/ijc.25334
DO - 10.1002/ijc.25334
M3 - Article
C2 - 20309937
AN - SCOPUS:78649571038
VL - 128
SP - 453
EP - 459
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 2
ER -