Palladium-spermine complex (Pd₂Spm) triggers autophagy and caspase-independent cell death in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which prompted the search for novel metal-based compounds. The dinuclear palladium(II)-spermine chelate (Pd₂Spm) has previously shown promising pharmacokinetics and in vivo antitumor effects. However, its impact towards chemotherapy-resistant TNBC is still to be addressed. This work developed a cell model of cisplatin resistance and compared the anticancer/antiproliferative effects of cisplatin (reference Pt-based drug) and Pd₂Spm in TNBC cells sensitive (MDA-MB-231) and resistant to cisplatin (MDA-MB-231/R). Pd₂Spm displayed a similar antiproliferative potency in MDA-MB-231 and MDA-MB-231/R cells, while cisplatin showed ca. 18-fold lower potency towards MDA-MB-231/R cells. When focusing on cell death, incubation of Pd₂Spm with either Necrostatin-1 (necroptosis inhibitor), Z-VAD (apoptosis inhibitor) or 3-Methyladenine (3-MA, autophagy inhibitor) showed that 3-MA can rescue Pd₂Spm-induced growth inhibition in MDA-MB-231 and MDA-MB-231/R cells. Furthermore, in MDA-MB-231 cells, Pd₂Spm triggered higher LC3-II levels and more profound Beclin-1 inhibition than cisplatin. Regarding apoptosis, Pd₂Spm did not induce the cleavage of caspase-3 and co-incubation with both Pd₂Spm and Z-VAD yielded only marginal effects in preventing the phosphatidylserine externalization compared to cisplatin. Thus, the present data provided more evidence on Pd₂Spm’s cell death mechanisms, triggering a caspase-independent cell death with autophagy involvement. In addition, the potential of Pd₂Spm to overcome chemotherapy resistance is promising.