JOIN USScientists at the Indian Institute of Science (IISc), Bengaluru, have discovered that certain iron containing chemical compounds can be used to kill cancerous cells.
Light acts as a switch that turns these compounds on and off. The compound is also unusual because it targets the powerhouse of the cell, the mitochondria. Prof Akhil Chakravarty from the Department of Inorganic and Physical Chemistry and Prof Paturu Kondaiah from the Department of Molecular Reproduction, Development and Genetics at IISc collaborated on a recent study published in the European Journal of Inorganic Chemistry. Their study combines the fields of inorganic chemistry and molecular genetics and looks at inorganic iron compounds as an alternative anti-cancer agent.
Mitochondria vs nucleus
This work targets the mitochondria of the cell as opposed to the nucleus (most studies target the nucleus, which is the part of the cell that contains most of its DNA). Mitochondria are subunits of our cells (called organelles) that are responsible for energy production. They even have their own set of DNA apart from what is present in the nucleus. Any mutation or dysfunction in the mitochondria can result in the disruption of energy production. The process of energy production from glucose is called glycolysis.
A disruption in this pathway can lead to a cancerous state. The body by itself normally destroys dysfunctional cells while checking for fully functioning cells. If the cells escape the body’s checking mechanism, they can go on to cause cancer. Hence, there is a need to develop ways to target these cells and prevent their proliferation in order to prevent the occurrence of cancer.
This study follows a new mode of cancer treatment called Photodynamic Therapy (PDT). Photosensitisers are light-sensitive compounds that can destroy target cells upon radiation. The study opts for inorganic metal complexes over the conventional organic molecules. The scientists discovered that a class of light-sensitive compounds (Inorganic Iron (III)-catecholates) causes cytotoxicity (toxicity to cells) upon irradiation with red light. Under red light, the compounds get activated and kill the tumour cells.
Traditionally, drugs such as cisplatin were used to target the nucleus of cells. This method saw an increasing number of cases of drug resistance. To combat this problem, the group of scientists designed and synthesised novel Iron (III)-catecholates that specifically target the mitochondria. In the presence of light, these compounds cleave the mitochondrial DNA and destroy the tumor cells.
Cytotoxicity check
The researchers designed the Iron (III)-catecholate complex to incorporate a positive TPP (TriPhenylPhosphine) moiety. They synthesised the complex through a complex set of chemical reactions. It was characterised for some physicochemical parameters and tested for stability. It was seen to absorb red light from the spectrum and get activated. They checked for the cytotoxicity (the ability to be toxic to a cell) of the compound in different cultures of mammalian cells: HeLa (human cervical cancer), MCF-7 (human breast cancer), A549 (human lung cancer) and HaCaT (human skin keratino-cyte).
Molecules called Reactive Oxygen Species (ROS) are produced from the complexes on photo-irradiation (and not in the dark) that cause damage to the cells. They trigger a cell-death pathway called apoptosis, where damaged cells are programmed to kill themselves (usually as a result of injury). Through microscopy studies, it was determined that this TPP moiety caused the generation of ROS specifically inside the mitochondria, triggering the cell death.
This work that took over three years to reach completion, differs vastly from the previous studies targeting cancer cells. Firstly, it targets the mitochondria of the cell as opposed to the nucleus to avoid the development of drug resistance. Secondly, it uses inorganic compounds instead of organic drugs. This successfully avoids the problems of skin sensitivity caused by organic drugs. Finally, this drug is extremely selective: it is activated exclusively in the presence of red light and shows no toxic behaviour in the dark.
This study has established that the drug can effectively bind to DNA, cleave it in the presence of light and specifically target certain subunits of the cell (in this case, the mitochondria). Thus, this work opens up innumerable prospects with respect to administering metal-based photodynamic therapeutic compounds as anti-cancer agents.
The next steps in this work would be establishing the function of this anti-cancer drug in animal models. It would then need to undergo further studies and clinical trials before going on the market. On being asked about what keeps him going, Prof Akhil said, “The aim is to help the cancer patients live better lives. If we can cure patients with cancer, that is more than what I can ask for.”
(The author is with Gubbi Labs, a Bengaluru-based research collective)