Glutathione Depleting a Chemoselective Novel Pro-oxidant Nano Metal–Organic Framework Induced G2/M Arrest and ROS-Mediated Apoptotic Cell Death in a Human Triple-Negative Breast Cancer Cell Line

Abstract

The progression of a new class of compounds to inhibit the uncontrolled proliferation of carcinoma cells has become one of the most powerful weapons to combat “cancer”. To this end, a new Mn(II)-based metal–organic framework, namely, [{Mn(5N3-IPA)(3-pmh)}(H2O)]α (5N3H2-IPA = 5-azidoisophthalic acid and 3-pmh = (3-pyridylmethylene)hydrazone), has been synthesized adopting a mixed ligand approach and exploited as a successful anticancer agent via systematic in vitro and in vivo studies. Single-crystal X-ray diffraction analyses depict that MOF 1 exhibits a 2D pillar-layer structure consisting of water molecules in each 2D void space. Due to the insolubility of the as-synthesized MOF 1, a green hand grinding methodology has been adopted to scale down the particle size to the nanoregime keeping its structural integrity intact. The nanoscale metal–organic framework (NMOF 1) adopts a discrete spherical morphology as affirmed by scanning electron microscopic analysis. The photoluminescence studies revealed that NMOF 1 is highly luminescent, enhancing its biomedical proficiency. Initially, the affinity of the synthesized NMOF 1 for GSH-reduced has been evaluated by various physicochemical techniques. NMOF 1 constrains the proliferation of cancer cells in vitro by inducing G2/M seizure and accordingly leads to apoptotic cell death. More significantly, compared to cancer cells, NMOF 1 exhibits less cytotoxicity against normal cells. It has been demonstrated that NMOF 1 interacts with GSH, causing a drop in cellular GSH levels and the production of intercellular ROS. It is quite intriguing that we discovered that NMOF 1-mediated ROS generation aids in significantly modifying the mitochondrial redox status, which is a crucial factor in apoptosis. According to mechanistic research, NMOF 1 increases the production of proapoptotic proteins and lowers the expression of antiapoptotic proteins, which significantly aids in activating caspase 3 and the subsequent cleavage of PARP1 and cell death via intrinsic apoptotic pathways. Finally, an in vivo investigation using immuno-competent syngeneic mice demonstrates that NMOF 1 can stop tumor growth without causing adverse side effects.

Cellular Alterations Due to Direct and Indirect Interaction of Nanomaterials with Nucleic Acids

“…The interaction of leached iron ions with DHA generated a substantial quantity of toxic •OH which, via ferroptosis triggering, eventually led to DNA damage, further confirming therapeutic efficacy in vivo [108]. In a similar way, complete manganese based-NMOF that leads to a reduction in GSH levels and thus, an increase in cytoplasmic and mitochondrial ROS generation, which led to DNA damage, has been developed [109].…”