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Characterization of Pt-, Pd-spermine complexes for their effect on polyamine pathway and cisplatin resistance in
Ramakumar Tummala1, Paula Diegelman, Sonia M Fiuza
1Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Abstract:
We have previously showed that platinum drugs up-regulate SSAT and SMO and down-regulate ODC and SAMDC in the polyamine pathway. Several studies including our own established that platinum drugs combined with polyamine analog DENSPM produces synergistic increase in SSAT activity with polyamine depletion. Since polyamine pathway is an important therapeutic target, we investigated whether agents containing both platinum and polyamines have similar effects on the polyamine pathway. Two complexes i) Pt-spermine with two cisplatin molecules linked to a spermine in the center and ii) Pd-spermine with similar structure i, but Pd (II) substituted for Pt (II) were analyzed with respect to their effect on the expression of genes in polyamine pathway, SSAT and SMO protein expression, SSAT activity and polyamine pools. Pt-, Pd-spermine complexes induced significant down-regulation of SMO, arginase 2 and NRF-2, with no change in SSAT, while cisplatin as a single agent or in combination with DENSPM induced significant up-regulation of SSAT and SMO. The SSAT activity was not induced by either Pt- or Pd-spermine in A2780 cells; SMO protein levels were significantly elevated compared to the no-drug control and to a similar extent as cisplatin/DENSPM. The Pd-spm treatment induced a fall in putrescine levels to 33%, spermidine to 62% and spermine to 72% while Pt-spm did not induce such a decline. Comparative cytotoxicity studies in A2780 cells indicated the potency to be cisplatin> Pd-Spm>Pt-Spm. Although both complexes exhibit a lower potency, the degree of resistance itself is much lower for Pt-spermine and Pd-spermine in that order (2.5 and 7.5, respectively) compared to cisplatin ( approximately 12) as tested in cisplatin resistant A2780/CP cells. These studies suggest that Pd (II)-polyamine complexes may constitute a promising group of inorganic compounds for further studies in the development of novel chemotherapy/adjuvant chemotherapy strategies.
Insights
New platinum and palladium-spermine complexes impact the polyamine pathway differently than traditional platinum drugs. These novel compounds show potential for developing new chemotherapy strategies with reduced resistance.
Area of Science:
- Inorganic chemistry
- Cancer biology
- Pharmacology
Background:
- Platinum-based drugs are crucial in cancer chemotherapy.
- The polyamine pathway is a significant therapeutic target in cancer treatment.
- Platinum drugs modulate polyamine pathway enzymes like SSAT and SMO.
Purpose of the Study:
- To investigate the effects of novel platinum (Pt) and palladium (Pd) spermine complexes on the polyamine pathway.
- To compare the effects of these complexes with cisplatin and cisplatin/DENSPM combination therapy.
- To evaluate the cytotoxicity and drug resistance profiles of Pt- and Pd-spermine complexes.
Main Methods:
- Synthesis and analysis of Pt-spermine and Pd-spermine complexes.
- Assessment of gene expression, protein levels (SSAT, SMO), and enzyme activity in the polyamine pathway.
- Measurement of polyamine pool levels (putrescine, spermidine, spermine).
- Cytotoxicity assays in A2780 and cisplatin-resistant A2780/CP cells.
Main Results:
- Pt- and Pd-spermine complexes down-regulated SMO, arginase 2, and NRF-2, unlike cisplatin which up-regulated SSAT and SMO.
- Neither Pt- nor Pd-spermine induced SSAT activity, but SMO protein levels increased.
- Pd-spermine significantly reduced putrescine, spermidine, and spermine levels.
- Cytotoxicity order was cisplatin > Pd-Spm > Pt-Spm.
- Pt- and Pd-spermine complexes exhibited significantly lower drug resistance compared to cisplatin in resistant cell lines.
Conclusions:
- Pd(II)-polyamine complexes demonstrate distinct effects on the polyamine pathway compared to platinum drugs.
- These complexes show promise as novel chemotherapy agents or adjuncts due to their efficacy and reduced resistance.
- Further research into Pd(II)-polyamine complexes is warranted for developing advanced cancer treatment strategies.
