(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.

• Keywords
• Anticancer, Cisplatin, DNA, Mechanism of action, Oxaliplatin, Phosphaplatin,
• MeSH
• Cisplatin pharmacology   MeSH
• Diphosphates pharmacology   MeSH
• DNA metabolism   MeSH
• Neoplasms * MeSH
• Organoplatinum Compounds pharmacology   metabolism   MeSH
• Oxaliplatin pharmacology   MeSH
• Platinum pharmacology   MeSH
• Antineoplastic Agents * pharmacology   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cisplatin MeSH
• Diphosphates MeSH
• diphosphoric acid MeSH Browser
• DNA MeSH
• Organoplatinum Compounds MeSH
• Oxaliplatin MeSH
• Platinum MeSH
• Antineoplastic Agents * MeSH

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal pharmacology   MeSH
• Diclofenac pharmacology   MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Neoplasms * MeSH
• Organoplatinum Compounds pharmacology   MeSH
• Platinum MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,10-phenanthroline MeSH Browser
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Diclofenac MeSH
• Ligands MeSH
• Organoplatinum Compounds MeSH
• Platinum MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.

• Keywords
• CAR T cells, antigen-presenting cells, chemotherapy, danger signals, dendritic cell, immune-checkpoint blockers, immunogenic cell death, immunotherapy,
• MeSH
• Cell Death MeSH
• Cytokines metabolism   MeSH
• Immunogenic Cell Death MeSH
• Humans MeSH
• Neoplasms * MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cytokines MeSH
• Antineoplastic Agents * MeSH