Platinum(IV)–Gold(I) Agents with Promising Anticancer Activity: Selected Studies in 2D and 3D Triple‐Negative Breast Cancer Models

Abstract

New heterometallic binuclear and trinuclear platinum(IV)‐gold(I) compounds of the type [Pt(L)nCl2(OH){(OOC‐4‐C6H4‐PPh2)AuCl}x] (L=NH3, n = 2; x = 1,2; L = diaminocyclohexane, DACH, n = 1; x = 2) are described. These compounds are cytotoxic and selective against a small panel of renal, bladder, ovarian and breast cancer cell lines. We selected a trinuclear PtAu2 compound containing the Pt(IV) core based on oxaliplatin, to further investigate its cell death pathway, cell and organelle uptake and anticancer effects against triple negative breast cancer (TNBC) MDA‐MB‐231 cell line. This compound induces apoptosis and accumulates mainly in the nucleus and mitochondria. It also exerts remarkable antimigratory and antiangiogenic properties, and has a potent cytotoxic effect against TNBC 3D spheroids. Trinuclear compounds do not seem to display relevant interactions with calf thymus (CT) DNA and plasmid (pBR322) even in the presence of reducing agents, but inhibit pro‐angiogenic enzyme thioredoxin reductase (TrxR) in TNBC cells.

Pt(iv) anticancer prodrugs bearing an oxaliplatin scaffold: what do we know about their bioactivity?

“…25). 94 The latter showed higher cytotoxic activities than oxaliplatin, cisplatin and the Au( i ) complex alone in MDA-MB-231 cells, and remarkable activities in SKOV3, A2780, Caki-1, T24, A549 cell lines. It also displayed the highest selectivity index towards malignant cells (7.7 vs. 1.9 and 2.7 for oxaliplatin and cisplatin).…”

Augmenting Cancer Therapy with a Supramolecular Immunogenic Cell Death Inducer: A Lysosome-Targeted NIR-Light-Activated Ruthenium(II) Metallacycle

“…Immunogenic cell death (ICD), a promising approach in anticancer immunotherapy, has garnered significant attention for its potential to elicit enduring antitumor immune responses, thereby preventing cancer recurrence and metastasis. − Hence, continuous efforts are directed toward developing innovative ICD inducers, particularly in the realms of chemotherapy and phototherapy, for immunotherapy against solid tumors. − Despite some pioneering examples, practical hurdles remain for the widespread application of established ICD inducers in immunotherapy. − On the one hand, the effectiveness of ICD-inducing immune responses is intricately linked to the production of reactive oxygen species (ROS). However, many ICD inducers struggle to generate sufficient intracellular ROS due to their intrinsic characteristics or a lack of organelle targeting ability, resulting in a low rate of immune responsiveness. − Furthermore, considering the limited diffusion radius (<0.02 μm) and the short lifespan (<0.04 μs) of ROS, most existing ICD inducers with unsatisfactory penetration and retention performance exhibit seriously compromised ROS generation in deep-seated solid tumors, thereby hindering therapeutic outcomes. − On the other hand, determining the minimal effective dose of an ICD inducer regimen, which maximizes immunological benefits while minimizing side effects, remains a formidable challenge. − For example, several chemotherapy-based ICD inducers (e.g., oxaliplatin) currently evoke ICD at a high dose (∼300 μM), potentially leading to unexpected adverse effects on healthy organs . Therefore, there is a pressing need to develop novel ICD inducers that can efficiently generate ROS and minimize adverse effects to activate immunomodulatory responses in deep solid tumors, even though this task remains challenging.…”