Danijela Niciforovic

Two new complexes [Pt(L1)Cl]Cl (Pt1) and [Pt(L2)Cl]Cl (Pt2), (L1 = N²,N⁶-bis(5-methylthiazol-2-yl)pyridine-2,6-dicarboxamide and L2 = N²,N⁶-di(benzo[d]thiazol-2-yl)pyridine-2,6-dicarboxamide), were synthesized and characterized. The rate of nucleophilic substitution reactions of complexes with l-methionine (l-Met), l-cysteine (l-Cys), and guanosine-5'-monophosphate (5'-GMP) decreases in the order of biomolecules reactivity: l-Met > l-Cys >5'-GMP. The complexes exhibited moderate binding affinity for calf thymus DNA and human serum albumin. Competitive binding studies of complexes with DNA in the presence of ethidium bromide and Hoechst 33258 revealed that minor groove binding is more dominant over intercalation. Pt1 was more selective and effective in decreasing the viability of 4T1 breast cancer cells by promoting both early- and late-stage apoptosis. The in vivo findings reinforced these results, demonstrating that Pt1 significantly reduced tumor growth while exhibiting minimal systemic toxicity. Molecular docking complemented experimental data, confirming DNA and HSA binding for both complexes, while Pt1 aligned better with pro-apoptotic activity under physiological conditions.

Immune Checkpoint Inhibitors (ICIs) are monoclonal antibodies that block inhibitory immune targets, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L). Pembrolizumab targets the PD-1 receptor of lymphocytes in lung cancer treatment. ICI checkpoint blockade enhances immunity against cancer cells. However, loss of immunoregulatory control can cause autoimmune reactions in various organs, leading to immune-related adverse events (irAEs). The most common irAE is ICIs-induced colitis, which usually develops 6–8 weeks after ICI initiation and can involve any part of the gastrointestinal system. Herein, we report a presentation of pembrolizumab-induced colitis in a female patient with metastatic lung cancer and review the most recent findings in the model of checkpoint-induced colitis. It was interesting to learn that the colon mucosa may show normal macroscopic findings, but microscopically, immunotherapy-induced autoimmune colitis could be present. Additionally, patients with grade 2 or higher symptoms should have a colonoscopy, receive systemic corticosteroids as treatment, and, based on their response, receive biologic therapy. Here, we present a case report of in a 45-year-old female who has been a smoker for 25 years, without comorbidities, and with metastatic lung cancer who developed colitis after the seventh cycle of pembrolizumab. This case presentation highlights the importance of early recognition and appropriate intervention in order to prevent permanent interruption of treatment with checkpoint inhibitors, as well as prevention of colitis complications.

Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration’s approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient’s condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.