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Halting the ABCs of cancer

Haven’t we all heard about drug-resistant bacteria that do not surrender to any antibiotic and turn deadly instead? Well, while we are still figuring out how to keep them in check, ‘drug-resistant cancer cells’ have risen their ugly heads. Cancer, the fatal disease that kills around 8.9 million people every year and is the second leading cause of death (the first being cardiovascular disease), has no known cure yet. Scientists have found out that akin to bacteria, cancerous cells also evade death by developing resistance to multiple pharmacological drugs. They do so by flushing out the drug from their inside and live another day. However, is there a way to stop them?

In a recent study, published in the journal Scientific Reports, researchers from the Indian Institute of Technology (IIT), Mandi, and the North Eastern Hill University, Shillong, have found molecules that could potentially stop cancer cells from flushing out drugs. This research could lead to a cure for multidrug resistance in cancer cells. The study was funded by grants from the Department of Science and Technology (DST), Ministry of Human Resource Development (MHRD) and the Science and Engineering Research Board (SERB).

All cells contain molecules called ‘protein pumps’ in their membranes, which are proteins acting as the cell’s defence mechanism. They expel drugs, ions and other foreign particles out of the cell. In multidrug resistant cancer cells, these protein pumps are present in excess and flush out all anticancer drugs from inside the cell with the help of adenosine triphosphate (ATP) molecules that are formed when glucose is broken down.

The ATP molecules bind to the protein pumps at specific regions called Nucleotide Binding Domains (NBDs). When these molecules are hydrolysed, they release energy that is used to transport molecules, like drugs, across the membrane. Hence, this binding is essential to remove drugs from the cell. Due to the importance of ATP in this process, the protein pumps involved in this process are called ATP Binding Cassette (ABC) transporters.

In the current study, the researchers aimed to identify a molecule that could potentially bind to the nucleotide binding domains of the protein pumps, instead of the ATP. This mechanism would then prevent the effluxing of drugs from the cell, making the cancerous cells vulnerable. They used a technique called molecular docking, which involves the superimposition of one molecule onto another using a computer program if the structures of both molecules are known. This technique can be used to identify protein-protein interactions, enzyme-substrate interactions, and drug-target interactions, among others.

The researchers used the nucleotide binding domain of the human multidrug resistance protein 1, which has already been studied in the past, for their research. This protein pump, although present in healthy cells, in cancer cells is present in much larger numbers, thereby failing chemotherapy. In this study, the researchers ‘docked’ a library of drugs approved by the FDA (Food and Drug Administration of the USA) for the treatment of other diseases onto this particular protein molecule.

The molecular docking studies showed that the drug potassium citrate had the highest binding affinity to the nucleotide binding domain of the human multidrug resistance protein 1. Potassium citrate is currently used as a drug to treat kidney stones and gout—a painful condition caused by the accumulation of urate crystals in the joints.

The researchers then carried out molecular dynamics simulations to understand the stability of the complex formed. They found that the complex formed between the nucleotide binding domain and potassium citrate is exceptionally stable.

“Therefore, potassium citrate can act as an inhibitor of human multidrug resistance protein 1 and thereby it has the potential to hamper the efflux of drug from the cancer cells”, state the researchers.

The researchers of the study suggest that further studies in animal models are needed to test the efficacy of this drug. Nevertheless, this study provides the first step towards a potential treatment against multidrug resistant cancer cells by targeting the ABCs of cancer cells.