Cisplatin Efficacy: The Importance of Measuring Uptake in Cancer Cells
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A platinum-based chemotherapy drug, cisplatin is used to treat a variety of different cancer types including; carcinomas, lymphomas and sarcomas.1 Although it was first synthesized in 1844 by the Italian chemist Michele Peyrone, it wasn’t until the 1960’s that the scientific community truly began to take notice of this compound’s potential. Research by scientists from Michigan State University identified by-products from platinum electrode activity were capable of inhibiting cell division in Escherichia coli.2 This discovery created interest in the possible use of platinum-based products (including cisplatin) as cancer chemotherapy agents.
Cisplatin was the first platinum compound to gain approval by the US Food and Drug Administration (FDA), in 1978. Its mechanism of action is through its ability to bind to DNA, via purine base crosslinking, forming DNA-platinum (Pt) adducts which are ‘bulky’ and result in DNA kinking. It is this kinking that inhibits DNA replication and subsequently induces cell apoptosis – unless the cells can repair the damage fast enough.3,4
Resistance to Cisplatin
Although cisplatin is clinically proven to combat numerous human cancers – bladder, head and neck, lung, ovarian, testicular – resistance to treatment remains a key challenge, and cisplatin patients can often relapse.
According to Dr. Chady Stephan, Senior Leader of Inorganic Applications at PerkinElmer: “Relapse frequently occurs due to the development of cisplatin resistance. There are a multitude of reasons why resistance occurs.”
The DNA kinking induced by the Pt adducts can be recognized and repaired by the nucleotide excision repair (NER) pathway. An increase in DNA repair is one molecular mechanism responsible for cisplatin drug resistance, along with increased cytosolic inactivation, and altered cellular accumulation of cisplatin.3
“Cellular uptake of cisplatin is related to tumor burden, meaning low intracellular cisplatin levels are associated with a decreased tumor response to cisplatin. There is a need to analyze the uptake and distribution of cisplatin at the level of a single cell to determine whether treatment is effective,” explains Dr. Stephan.
The amount of cisplatin imported in to the cell impacts the amount of cell damage that occurs; the greater the uptake the more DNA damage, meaning more frequent cellular apoptosis. Having the ability to understand and determine the cellular uptake of cisplatin is key to developing novel strategies and therapies to increase tumor cell sensitivity to cisplatin.
Analyzing Cisplatin Uptake and Distribution
To determine whether treatment is effective the uptake and distribution of cisplatin must be measured at the level of a single cell. However, traditional strategies for analyzing the uptake are limited to measuring the total Pt concentration in a population of cells which have been digested.4
“Traditional methods to measure cisplatin uptake yield a single value that represents an entire cellular population. The variation of uptake from cell to cell cannot be captured utilizing traditional methods.” says Dr. Stephan.
A novel approach has now been developed that enables the quantitation of Pt at the level of a single cell. Dr. Stephan describes the new method: “Single Cell ICP-MS (SC-ICP-MS) is an emerging technique developed to address the need to quantify cisplatin (or other metals) levels in a single cell. SC-ICP-MS is based on the ability to measure discrete signals generated from a single cell once it enters the plasma producing an ion cloud.”
“With a data acquisition speed of 100,000 points per second and a dedicated sample introduction system that ensures the delivery of the cells to the ICP-MS plasma, the metal content of a single cell can be quantified down to the attogram (ag) per cell level.”
Analyzing Cisplatin Uptake: Benefits of Single Cell ICP-MS
In comparison to traditional methods, this approach yields far more information. Thousands of single cells can be measured and the distribution of cisplatin uptake within a population can be obtained. “This gives scientists a new understanding of cisplatin uptake allowing for the development of new strategies and therapies to increase tumor sensitivity to cisplatin.” says Dr. Stephan.
“Future studies using single cell ICP-MS would potentially identify novel pathways that influence cellular cisplatin import and export the cells to increase responsiveness to cisplatin chemotherapy.” explains Dr. Stephan. “The molecular identification of cells that are the low responders to cisplatin treatment would be useful in the recognition of the development of cisplatin resistance.”
1. Dasari, S. and Bernard Tchounwou, P. (2014). Cisplatin in cancer therapy: Molecular mechanisms of action. European Journal of Pharmacology, 740, pp.364-378.
2. Rosenberg, B., Van Camp, L. and Krigas, T. (1965). Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode. Nature, 205(4972), pp.698-699.
3. Amable, L. (2016). Cisplatin resistance and opportunities for precision medicine. Pharmacological Research, 106, pp.27-36.
4. New Research Evaluating Cisplatin Uptake in Ovarian Cancer Cells by Single Cell ICP-MS. Link: http://www.perkinelmer.com/lab-solutions/resources/docs/APP-NexION-2000-ICP-MS-Single-Cell-Cancer-Research-013176_01.pdf