Multipronged Protein Engagement by a Ruthenium(II) Sunitinib Hydrazide Complex Elicits ROS‐Independent Immunogenic Cell Death
Abstract
ABSTRACT Metal‐based immunogenic cell death (ICD) inducers commonly rely on elevated reactive oxygen species (ROS) to trigger endoplasmic reticulum (ER) stress. The central regulator of inflammatory signaling, NF‐κB, can amplify oxidative stress responses and promote pro‐tumorigenic signaling. Thus, strategies that induce ICD independently of ROS may represent a conceptual shift from ROS‐driven paradigms. Here we show that using a hydrazide derivative of a clinical angiogenesis inhibitor sunitinib to form a Ru(II)–sunitinib hydrazide complex ( 5 ) inhibits NF‐κB signaling (reduced p65 phosphorylation and blocked p50–p65 nuclear translocation), suppresses VEGFR2 phosphorylation, and decreases telomerase activity (cell‐free TRAP assay), thereby redirecting cellular responses toward apoptotic ICD. The sunitinib hydrazide provides the VEGFR2 and telomerase inhibition properties but it also promotes NF‐κB (p50–p65) nuclear translocation and ROS generation. In contrast, the intracellular ROS levels remain largely unchanged with 5 which inhibits the NF‐κB pathway. Simultaneous inhibition of VEGFR2, NF‐κB, and telomerase enforces sustained non‐oxidative ER–mitochondrial stress, triggering DAMP release and apoptotic immunogenic cell death. Folate‐targeted PEG–PCL micellar delivery ( 5@PFC ) improves tumor selectivity fourfold and suppresses tumor growth in immunocompetent 4T1 mice, accompanied by an increased intratumoral CD4:CD8 ratio, indicating enhanced immune activation.
Article Details
Authors (15)
Shilpendu Ghosh
Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM), Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
Soumee SenGupta
Ratan Halder
Polymer Research Centre, Centre for Advanced Functional Materials Institution Indian Institute of Science Education and Research Kolkata Mohanpur India
Sayar Ghosh
Department of Biological Sciences Institution Indian Institute of Science Education and Research Kolkata Mohanpur India
Soumyajit Biswas
Department of Biochemistry & Biophysics University of Kalyani Kalyani India
Sujato Mukherjee
Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM) Indian Institute of Science Education and Research Kolkata Mohanpur India
Moumita Gupta
Polymer Research Centre, Centre for Advanced Functional Materials Institution Indian Institute of Science Education and Research Kolkata Mohanpur India
Banshi Roy
Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM), Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
Liebig Ranjan Debnath
Department of Biochemistry & Biophysics University of Kalyani Kalyani India
Rima Das
Department of Biochemistry & Biophysics University of Kalyani Kalyani India
Raja Shunmugam
Polymer Research Centre, Centre for Advanced Functional Materials Institution Indian Institute of Science Education and Research Kolkata Mohanpur India
Utpal Ghosh
Department of Biochemistry & Biophysics University of Kalyani Kalyani India
Amirul Islam Mallick
Department of Biological Sciences Institution Indian Institute of Science Education and Research Kolkata Mohanpur India
Rahul Das
Arindam Mukherjee
Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM), Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India