Different cell cycle kinetic effects of N 1,N 11-diethylnorspermine-induced polyamine depletion in four human breast cancer cell lines

Abstract

Polyamine analogues are presently undergoing clinical evaluation in the treatment of cancer. To better understand under what circumstances treatment with a polyamine analogue will yield beneficial results, we have investigated the effect of N,N-diethylnorspermine (DENSPM) on cell cycle kinetics of the human breast cancer cell lines SK-BR-3, MCF-7, HCC1937, and L56Br-C1. A bromodeoxyuridine-DNA flow cytometry method was used to evaluate the treatment with 10 micromol/l DENSPM on cell cycle kinetics. A correlation between polyamine pool size after DENSPM treatment and cell cycle kinetic effects was found. The most sensitive cell cycle phase was the S phase, followed by an effect on the G2+M phase and then the G1/S transition. The levels of a number of cell cycle regulatory proteins such as cyclin E1, cyclin A2, and cyclin B1 were lowered by DENSPM treatment, which may explain the effects on cell cycle kinetics. The two cell lines that were most sensitive to DENSPM treatment belong to the basal-like subtype of breast cancer and they were deficient with respect to p53, BRCA1, and RB1.

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

“…The least sensitive cell MCF-7 has wild-type p53 and this may implicate that normal cells that have wild-type p53 may not be severely injured by DENSPM treatment. We have shown that MCF-7 cells have a wild-type p53-dependent response with a G 1 accumulation in the cell cycle distribution as an effect of polyamine analogue treatment [41]. Similar results have previously been described by Kramer et al [65], in which they treated wild-type p53 containing MALME-3M cells with DENSPM.…”

“…It should be pointed out that all the DENSPM-induced responses in L56Br-C1 cells are p53 and pRB independent [41]. This is favourable from a cancer treatment point of view as the nonfunctional forms of these proteins have been associated with resistance to chemotherapeutic intervention [64].…”

“…Polyamine pool depletion results in inhibition of cell proliferation in all four-cell lines but with different kinds of kinetics [41]. The most extensive decrease in the polyamine pools was, however, found in L56Br-C1 cells where apoptosis is induced.…”

“…Although cell proliferation is always inhibited in cells where polyamine depletion is taking place, the rate with which this takes place differs between different cell lines. We have performed an extensive study of the effect of DENSPM treatment on cell cycle kinetics in the four breast cancer cell lines used in this study [41]. The most interesting aspect of polyamine depletion from a cancer treatment point of view is the induction of apoptosis.…”

Silencing of the polyamine catabolic key enzyme SSAT prevents CDK inhibitor-induced apoptosis in Caco-2 colon cancer cells

“…Genetic alterations in the regulation of the natural PAs Put, Spd and Spm which are essential for cell growth and differentiation may induce cell cycle arrest and apoptosis in various cancer cell lines (36). Recent studies have indicated that chemotherapeutic agents, such as cisplatin, paclitaxel, doxorubicin, 5-FU and oxaliplatin, may induce SSAT expression and decrease total PA content in cells (37,38).…”