Abstract
Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.
Highlights
Drug resistance is a major obstacle in successful chemotherapy of metastatic breast cancer and most patients with drug resistant metastatic cancer succumb to the disease
This study provides evidence that apoptotic response in antimetabolite drug-treated tumor cells involves enhanced cyclin A/cdk2 activity concomitant with increased E2Fl DNA binding activity. Taken together these results suggest that cyclin A and associated kinase activity are regulators of a checkpoint response that is activated in drug-treated cells leading to induction of apoptosis
It has been hypothesized that loss of apoptotic response often leads to chemotherapy resistance in cancer cells
Summary
Drug resistance is a major obstacle in successful chemotherapy of metastatic breast cancer and most patients with drug resistant metastatic cancer succumb to the disease. It is important to investigate the genetic basis of drug resistance in metastatic cancer cells to design effective therapy of advanced stage disease and improve their clinical outcome. Increased genetic instability leads to progressive metastasis of tumors with simultaneous acquisition of resistance to chemotherapeutic drugs. Recent advances in understanding the mode of action of anticancer drugs indicate that regardless of their diverse nature, most of them elicit apoptosis in the target cells [1,2]. The genetic changes which inactivate apoptotic pathways during tumor development make tumor cells resistant to drugs. Premature activation of a subset of protein kinases, normally active in mitosis, has been implicated as critical events in the apoptosis process [5,6]
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