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.

Keywords: antineoplastic activity; antiproliferative; cancer resistance; cell viability; cisplatin; palladium; platinum; therapy.

Figure 1

Structure of Pt(II)- and Pd(II)-based agents: Pd(II) or Pt(II) trinuclear chelates with spermidine, Pd₃Spd₂ or Pt₃Spd₂; conventional mononuclear Pt(II) drug—cisplatin and Pd(II) dinuclear chelates with spermine Pd₂Spm.

Figure 2

Impact of increasing concentrations of Pd₃Spd₂ or Pt₃Spd₂ on TNBC proliferation. Dose–response curves of Pd₃Spd₂ (upper panel) and Pt₃Spd₂ (lower panel) in breast cancer MDA-MB-231 and MDA-MB-231/R cells at 24, 48 and 72 h of incubation. Values are expressed as the mean ± SEM from 4 independent experiments (in triplicate) analyzed with nonlinear regression and the Student’s t-test. Data points with no visible error bars have errors smaller than the size of the symbol.

Figure 3

Representative photomicrographs with morphological features induced by increasing concentrations of Pd₃Spd₂ (A) or Pt₃Spd₂ (B) incubated for 48 h in MDA-MB-231 cells or MDA-MB-231/R cells. White arrows show cytoplasmic shrinkage and the rounding of cells. Representative images from 4 independent experiments obtained under an objective lens of a phase contrast of the LionheartFX microscope. Scale bar = 100 μm.

Figure 4

Impact of increasing concentrations of Pd₃Spd₂ or Pt₃Spd₂ on TNBC. Dose–response curves of Pd₃Spd₂ (upper panel) and Pt₃Spd₂ (lower panel) in breast cancer MDA-MB-231 and MDA-MB-231/R cells at 24, 48 and 72 h of incubation obtained through the MTT assay. Values are expressed as the mean ± SEM from 4 independent experiments (in triplicate) analyzed with nonlinear regression. Data points with no visible error bars have errors smaller than the size of the symbol.

Figure 5

Impact of increasing concentrations of Pd₃Spd₂, cisplatin or Pd₂Spm on TNBC sensitive and resistant to cisplatin incubated for 48 h. Dose–response curves in breast cancer MDA-MB-231 cells (sensitive to cisplatin, (left panel) line) and MDA-MB-231/R cells (resistant to cisplatin, (right panel)) at 48 h of incubation. Values are expressed as the mean ± SEM from 4 independent experiments (in triplicate) analyzed with nonlinear regression and the Student’s t-test. Data points with no visible error bars have errors smaller than the size of the symbol.

Figure 6

Impact of increasing concentrations of Pd₃Spd₂, Pd₂Spm or cisplatin on breast healthy cells (MCF-12A) incubated with the drug for 48 h. (A) Dose–response curves for cell proliferation. Values are expressed as the mean ± SEM from 4 independent experiments (in triplicate) analyzed with nonlinear regression and the Student’s t-test. Data points with no visible error bars have errors smaller than the size of the symbol. (B) Representative photomicrographs showing morphological changes. White arrows show cytoplasmic shrinkage and the rounding of cells. Representative images from 4 independent experiments obtained under an objective lens of a phase contrast of the LionheartFX microscope. Scale bar = 100 μm.