Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10–20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes’ ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65–8.99 µM and 9.24–13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.

Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

“…The cytotoxicity of Pd 2 Spm on R cells (IC 50 10.6 μM) is promisingly higher than that of cDDP in the same cells (32.4 μM) . It is noteworthy that the metabolic impact of Pd 2 Spm on R cells is stronger compared to that of S cells, for instance, in terms of amino acid depletion at 24 h, with hardly any recovery of amino acid levels at 48 h (in contrast with cDDP/R cells).…”

“…The cytotoxicity of Pd 2 Spm on R cells (IC 50 10.6 μM) is promisingly higher than that of cDDP in the same cells (32.4 μM). 27 It is noteworthy that the metabolic impact of Pd 2 Spm on R cells is stronger compared to that of S cells, for instance, in terms of amino acid depletion at 24 h, with hardly any recovery of amino acid levels at 48 h (in contrast with cDDP/ R cells). This may indicate that amino acid metabolism in R cells is not as resistant to Pd 2 Spm as it seems to be in relation to cDDP at 48 h. In addition, as the amino acid signature of Pd 2 Spm/R cells includes the changes noted in S cells as possibly indicating a positive response to treatment (namely, decreased aspartate, glutamate, lysine, NAA, and PCr and increased taurine), we postulate that such behavior in R cells treated with Pd 2 Spm may reflect the higher cytotoxicity of the Pd(II) complex against R cells.…”

“…28 The high ATP consumption in the presence of cDDP (ATP probably arising through the increased TCA cycle activity and lipid oxidation) may be related to meeting the energy demands of membrane PL biosynthesis and pyrimidine metabolism. CDDP treatment of R cells is characterized by more than one order of magnitude higher IC 50 (32.4 μM), 27 which clearly reflects resistance of the cells to cDDP treatment. The metabolic profile of R cells is more responsive to cDDP than that of S cells, which may reflect some kind of protective behavior against the drug to avoid/reduce cell death.…”

“…MDA-MB-231 cells were cultured in DMEM-HG cell growth medium supplemented with 10% (v/v) FBS and maintained under a humidified atmosphere of 5% CO 2 at 37 °C. The cDDP-resistant cell line was established as previously described (exposure of MDA-MB-231 cells to increasing concentrations of cDDP, up to a maximum of 2 μM, during 6 months), and it was designated as MDA-MB-231/ R. 27 Cell population doubling times were 25.5 ± 0.9 and 30.6 ± 1.1 h for MDA-MB-231 and MDA-MB-231/R cells, respectively. Cell cultures were routinely screened for mycoplasma contamination, with all assays having yielded negative results.…”

“…20,21 In an attempt to address cDDP resistance, the biochemical effects of Pd(II) agents on cDDP-sensitive and cDDP-resistant MDA-MB-231 cells have been investigated. 27 The trinuclear chelate with spermidine (Spd, H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH 2 ), Pd 3 Sdp 2 , was compared with its Pt(II)-analog Pt 3 Spd 2 , Pd 2 Spm and cDDP. The Pd(II) complexes exhibited similar enhanced antiproliferative effects in resistant cells compared to cDDP, whereas cDDP remained the most cytotoxic agent for sensitive cells (IC 50 after 48 h: cDDP 1 μM; Pd 2 Spm 7.90 μM; Pd 3 Spd 2 8.44 μM).…”