Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

Abstract

Cancer cells can overcome the ability of polyamine biosynthesis inhibitors from completely depleting their internal polyamines by the importation polyamines from external sources. We have developed a group of lipophilic polyamine analogs that potently inhibit the cellular polyamine uptake system and greatly increase the effectiveness of polyamine depletion when used in combination with DFMO, a well-studied polyamine biosynthesis inhibitor. By the attachment of an length-optimized C 16 lipophilic substituent to the epsilon-nitrogen atom of our earlier lead compound, D-Lys-Spm (5), we have produced an analog, D-Lys(C 16 acyl)-Spm (11) with several orders of magnitude more potent cell growth inhibition on a variety of cultured cancer cell types including breast (MDA-MB-231), prostate (PC-3), melanoma (A375) and ovarian (SK-OV-3), among others. We discuss these results in the context of a possible membrane-catalyzed interaction with the extracellular polyamine transport apparatus. The resulting novel two-drug combination therapy targeting cellular polyamine metabolism has shown exceptional efficacy against cutaneous squamous cell carcinomas (SCC) in a transgenic ornithine decarboxylase (ODC) mouse model of skin cancer. A majority (88%) of large, aggressive SCCs exhibited complete or near-complete remission to this combination therapy, while responses to each agent alone were poor. The availability of a potent polyamine transport inhibitor allows, for the first time, for a real test of the hypothesis that starving cells of polyamines will lead to objective clinical response.

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

“…A novel Polyamine Blocker Therapy (PBT) has recently been described that includes the use of DFMO to block polyamine biosynthesis along with AMXT 1501 as an inhibitor of polyamine transport. AMXT 1501 is designed as a polyamine mimetic and consists of a lysine-spermine backbone with a C 16 lipophilic substituent added to the ε-amino group of the lysine portion to optimize its ability to block cellular uptake of spermidine in the nanomolar range without crossing the cell membrane (24). Analyses of AMXT 1501 uptake into tumor cells in culture following a 24-hour incubation with 10 µM AMXT 1501 found no intracellular uptake (24).…”

“…AMXT 1501 is designed as a polyamine mimetic and consists of a lysine-spermine backbone with a C 16 lipophilic substituent added to the ε-amino group of the lysine portion to optimize its ability to block cellular uptake of spermidine in the nanomolar range without crossing the cell membrane (24). Analyses of AMXT 1501 uptake into tumor cells in culture following a 24-hour incubation with 10 µM AMXT 1501 found no intracellular uptake (24). Additionally, no rescue from the growth inhibitory effects of DFMO occurred when AMXT 1501 was given to cells in the absence of exogenous spermidine, suggesting that AMXT 1501 by itself or its metabolites cannot replenish cellular polyamine requirements.…”

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

“…Studies using both ODC (DFMO) and PAT inhibitors to treat PCP are being conducted. This combination therapy is expected to be a more effective PCP treatment, as a synergistic effect has been shown in cancer therapy (5,7). Because of a limited supply of the compound, only one dosage and one treatment condition were tested in the current study.…”

Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect

“…The efficiency of the polyamine transport system (PTS) is also greatly increased in tumoral cells. This property is of potential interest for targeting antitumor agents [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Based on these observations, we have developed a new generation of iron chelators, the Quilamines, in which an 8-hydroxyquinoline chelating subunit is grafted onto polyamine vectors, in order to vectorize the iron chelator inside the cancerous cell with an overactive PTS [29].…”