Metal complexes of NSAIDs as potent anti-tumor chemotherapeutics: Mechanistic insights into cytotoxic activity via multiple pathways primarily by inhibition of COX–1 and COX–2 enzymes

•Metal complexes of NSAIDs hold promising therapeutic potential to treat cancer.•NSAID scaffolds tethered with metal complexes exhibit greatly enhanced pharmacological activity.•They exhibit better cytotoxicity by targeting multiple signaling pathways.•NSAID metal complexes can target Cancer Stem cells and resistant cancer cells thereby, can act as efficacious anti-cancer therapeutics. Non–steroidal anti-inflammatory drugs (NSAIDs) have gained considerable attention due to their well–established medicinal properties such as anti-inflammatory, anti-bacterial, anti-tumor, anti-proliferative and analgesic. Recently, metal complexes of NSAIDs have attracted much more focus as compared to free NSAIDs in anti-tumor drug regime, as it has been proven in literature that therapeutic potency of drugs is greatly enhanced on complexation. By selecting the suitable metal ion, its oxidation state, charge as well as coordination geometry, we can easily fine tune the NSAID–metal conjugates for specific targeted therapies. Metal complexes have an intriguing behavior in vivo due to their interesting redox states or catalytic centers, thermodynamic stability, have ability to interact with intracellular components and target biomolecules viz, DNA, RNA and proteins, coordination environment that can drastically change their biology and toxicity properties and show distinctive recognition of normal vs cancerous cells. Interestingly, metals belonging to same group and period may behave differently in biological environment and therefore, complexes of elements from different or same groups or blocks offer discrete chemistry and biological mechanistic insights in cell inhibition processes which needs close and careful introspection. In this review, we would like to summarize the recent developments of myriad NSAIDs complexes in last decade viz., (i) main group metals (ii) transition metals (iii) metalloids (iv) lanthanides and v) mixed group metallodrug NSAID conjugates and their mechanistic insights of cytotoxic activity. Future prospects of NSAIDs–metalloconjugates as a prominent class of potent chemotherapeutic drug candidates shall also be discussed.