The Next Generation of Anticancer Metallopharmaceuticals: Cancer Stem Cell‐Active Inorganics

Abstract

Cancer stem cells (CSCs) are heavily linked to fatal incidences of cancer relapse and metastasis. Conventional cancer therapies such as surgery, chemotherapy and radiation are largely futile against CSCs. Therefore, highly original approaches are needed to overcome CSCs and to provide durable, long-term clinical outcomes. Many academia- and pharmaceutical-led studies aimed at developing chemical or biological anti-CSC agents are ongoing; however, the application of inorganic compounds is rare. In this minireview, we discuss how the chemical diversity and versatility offered by metals has been harnessed to develop an unprecedented, emerging class of metallopharmaceuticals: CSC-active inorganics. A detailed account of their mechanism(s) of action is provided, and possible future directions for exploration are also put forward.

Synthesis, Characterisation and In Vitro Anticancer Activity of Catalytically Active Indole-Based Half-Sandwich Complexes

“…Cancer is the second leading cause of death globally, with an estimated 9.6 million deaths in 2018 [ 1 ]. There is a need for the development and screening of anticancer therapeutics with non-conventional mechanisms of action (MoAs) [ 2 , 3 , 4 ]. Metallodrugs can provide rich chemistry and unique MoAs owing to their versatile structures, geometries and reactivities: examples include polypyridyl octahedral complexes of precious metals, some of which have been shown to target mitochondria and generate high levels of reactive oxygen species (ROS), while others can act as photosensitisers for use in photodynamic therapy [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ], and half-sandwich complexes of metals from groups eight and nine (Fe, Ru, Os; Co, Rh, Ir) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Platinum (IV) Derivatives with Cinnamate Axial Ligands as Potent Agents Against Both Differentiated and Tumorigenic Cancer Stem Rhabdomyosarcoma Cells

“…In contrast, conventional cyclophosphamide showed relatively high IC 50 values ranging from 41 μ m on RD CD133− up to 71 μ m on MCF‐7 CD44+ thus being 88–187‐fold less potent than complex 2 . Antiproliferative activity of cisplatin was also in μ m range; moreover, cisplatin was more effective in differentiated cancer cells (MCF‐7 CD44− and RD CD133− ) than in CSC cells (MCF‐7 CD44+ and RD CD133+ ), in accord with the known no CSC‐potency of cisplatin . Importantly, the data shows that 1 and 2 can kill both CSC‐enriched and CSC‐depleted cells with similar efficiency.…”

Polypyridyl Zinc(II)-Indomethacin Complexes with Potent Anti-Breast Cancer Stem Cell Activity

“…The ineffectiveness of 2 against mammospheres (IC 50 > 133 µM) ( Figure 2 C) was surprising considering its high potency (sub-micromolar) against monolayer cell cultures of HMLER-shEcad cells ( Table 1 ). The zinc(II) complexes, 3 – 5 displayed similar mammosphere potency to analogous copper(II)-phenanthroline-indomethacin complexes [ 13 ], indicating that redox activity may not be vital for anti-CSC activity within this class of metal-phenanthroline-NSAID complexes.…”

“…There are many academic- and pharmaceutical-led research programs underway with the aim of developing clinically viable anti-CSC agents, however, most of them have focused on biologics or purely organic compounds [ 12 ]. We and others have recently shown that the diversity and versatility of metals can be harnessed to develop inorganic compounds with promising anti-CSC activities [ 13 ].…”