TY - JOUR
T1 - Development of resistance to a trinuclear platinum complex in ovarian carcinoma cells
AU - Perego, Paola
AU - Gatti, Laura
AU - Righetti, Sabina C.
AU - Beretta, Giovanni L.
AU - Carenini, Nives
AU - Corna, Elisabetta
AU - Dal Bo, Laura
AU - Tinelli, Stella
AU - Colangelo, Donato
AU - Leone, Roberto
AU - Apostoli, Piero
AU - Lombardi, Luciano
AU - Beggiolin, Gino
AU - Piazzoni, Laura
AU - Zunino, Franco
PY - 2003/7/10
Y1 - 2003/7/10
N2 - BBR3464 is a trinuclear platinum complex that exhibits a potent cytotoxicity and efficacy against cisplatin-resistant tumors. To better understand the determinants of cellular resistance to BBR3464, we selected a resistant ovarian carcinoma cell line after exposure to the complex. The resistant cells (A2780/BBR3464) exhibited a high level of resistance to the selecting agent, but a marginal cross-resistance to cisplatin. Although cellular accumulation of BBR3464 was similar in parental and in resistant cells, DNA platination was decreased in A2780/BBR3464 cells, suggesting a reduced drug accessibility to DNA. This behavior reflected a partial drug inactivation at cytoplasmic level, as a consequence of increased levels of nucleophilic molecules including metallothioneins and human neurofilament low, but not glutathione. A2780/BBR3464 cells also exhibited a reduced susceptibility to apoptosis, which was consistent with reduced expression of Bax, and an alteration of DNA mismatch repair system, as reflected by lack of expression of MLH1 and PMS2, which could impair the recognition/repair of DNA lesions. Whereas both platinum drugs induced G2/M arrest in the parental cells, BBR3464, but not cisplatin, caused a late G1 arrest of resistant cells. Cisplatin induced an appreciable increase of p21wAF1 levels in both models, in contrast to BBR3464 that produced a substantial upregulation of p21WAF1 only in parental cells. An inverse relationship with p21WAF1 modulation was found for CHK1 in parental cells treated with both agents and in resistant cells treated with cisplatin. This pattern of response is consistent with a regulatory loop involving p53 and p21WAF1 at G2 checkpoint. In contrast, no modulation of CHK1 was found in A2780/BBR3464 treated with the triplatinum compound. These findings, indicating a different activation of regulatory pathways at DNA damage checkpoints in response to cisplatin and BBR3464, support an altered ability of resistant cells to recognize or tolerate sublethal lesions induced by BBR3464.
AB - BBR3464 is a trinuclear platinum complex that exhibits a potent cytotoxicity and efficacy against cisplatin-resistant tumors. To better understand the determinants of cellular resistance to BBR3464, we selected a resistant ovarian carcinoma cell line after exposure to the complex. The resistant cells (A2780/BBR3464) exhibited a high level of resistance to the selecting agent, but a marginal cross-resistance to cisplatin. Although cellular accumulation of BBR3464 was similar in parental and in resistant cells, DNA platination was decreased in A2780/BBR3464 cells, suggesting a reduced drug accessibility to DNA. This behavior reflected a partial drug inactivation at cytoplasmic level, as a consequence of increased levels of nucleophilic molecules including metallothioneins and human neurofilament low, but not glutathione. A2780/BBR3464 cells also exhibited a reduced susceptibility to apoptosis, which was consistent with reduced expression of Bax, and an alteration of DNA mismatch repair system, as reflected by lack of expression of MLH1 and PMS2, which could impair the recognition/repair of DNA lesions. Whereas both platinum drugs induced G2/M arrest in the parental cells, BBR3464, but not cisplatin, caused a late G1 arrest of resistant cells. Cisplatin induced an appreciable increase of p21wAF1 levels in both models, in contrast to BBR3464 that produced a substantial upregulation of p21WAF1 only in parental cells. An inverse relationship with p21WAF1 modulation was found for CHK1 in parental cells treated with both agents and in resistant cells treated with cisplatin. This pattern of response is consistent with a regulatory loop involving p53 and p21WAF1 at G2 checkpoint. In contrast, no modulation of CHK1 was found in A2780/BBR3464 treated with the triplatinum compound. These findings, indicating a different activation of regulatory pathways at DNA damage checkpoints in response to cisplatin and BBR3464, support an altered ability of resistant cells to recognize or tolerate sublethal lesions induced by BBR3464.
KW - Ovarian carcinoma
KW - Platinum drugs
KW - Resistance
UR - http://www.scopus.com/inward/record.url?scp=0037837096&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037837096&partnerID=8YFLogxK
U2 - 10.1002/ijc.11140
DO - 10.1002/ijc.11140
M3 - Article
C2 - 12740909
AN - SCOPUS:0037837096
VL - 105
SP - 617
EP - 624
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 5
ER -