The role of spermidine/spermineN1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells

Abstract

Polyamines have been shown to play a role in the growth and survival of several solid tumors, including colorectal cancer. We identified the polyamine catabolic enzyme spermidine/spermine N 1 -acetyltransferase (SSAT) as being one of the most highly inducible genes in two DNA microarray screens to identify novel determinants of response to chemotherapeutic agents in colorectal cancer. SSAT was shown to be inducible in response to 5-fluorouracil (5-FU) or oxaliplatin in parental and drugresistant HCT116 cell lines. It was also shown that SSAT mRNA was up-regulated in response to 5-FU or oxaliplatin in a panel of six colorectal cancer cell lines.

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

“…In particular, we observed a concordant modulation at every time point of SAT-1 and SRM, both involved in the cellular polyamine metabolism [37]. The concerted up and downregulation of the catabolic SAT-1 and the biosynthetic SRM enzyme, respectively, is expected to result in a reduction of the cellular polyamine pools, a condition associated with growth inhibition and apoptosis [38]. Indeed, targeting the polyamine pathway may have clinical relevance in anticancer therapy 3 .…”

Characterization of Pt-, Pd-spermine complexes for their effect on polyamine pathway and cisplatin resistance in A2780 ovarian carcinoma cells

“…DENSPM up-regulates SSAT and down-regulates the biosynthetic pathway enzymes ODC and SAMDC causing depletion of polyamine pools and this analog has been tested in Phase I and Phase II clinical trials (13)(14)(15)(16) and had no demonstrable single agent activity. Our studies and others have shown that when platinum drugs are combined with DENSPM, the synergistic SSAT activity and polyamine pool depletion that occurs in tumor cells is significantly greater than that by either of the single agents (7,17,18). The biogenic polyamine spermine is able to form chelates with several metal ions providing flexible linkers and conferring hydrophobic character to the molecule, which is important for drug uptake and enables a distinct interaction with DNA when compared to cisplatin.…”

“…A significant body of studies accumulated in the last several years indicate that platinum drugs have an effect on the polyamine pathway (6,7,17,18,35,36). Our own Affymetrix experiments with oxaliplatin and cisplatin indicate that both of these drugs up-regulated the polyamine catabolic pathway enzymes SSAT and SMO and down-regulated the biosynthetic pathway enzymes SAMDC and ODC (6).…”

“…Our own Affymetrix experiments with oxaliplatin and cisplatin indicate that both of these drugs up-regulated the polyamine catabolic pathway enzymes SSAT and SMO and down-regulated the biosynthetic pathway enzymes SAMDC and ODC (6). A study from our laboratory and others have shown that while platinum drugs are potent inducers of SSAT gene expression, the gene expression does not translate into activity (7,17,18). However, when oxaliplatin is combined with a polyamine analog such as DENSPM a synergistic increase in SSAT activity occurs (7,17,18) with concurrent polyamine pool depletion (7,17).…”

“…A study from our laboratory and others have shown that while platinum drugs are potent inducers of SSAT gene expression, the gene expression does not translate into activity (7,17,18). However, when oxaliplatin is combined with a polyamine analog such as DENSPM a synergistic increase in SSAT activity occurs (7,17,18) with concurrent polyamine pool depletion (7,17). We hypothesized that Pt-, Pd-spermine complexes may possibly have an impact on polyamine pathway and polyamine pools since they represent a composite of two cisplatin molecules (or Pd-diammine dichloride molecules) that are linked to a spermine in the center.…”