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

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.