3D reconstruction of whole-cell volumes by tomography of cells treated with cisplatin and tricine. Images obtained at the MISTRAL beamline of ALBA. On the right, colors show surface boundaries identifying different organelles in the cisPt-tricine-treated cell: mitochondria (yellow), the nucleus (blue), endosomes and/or lysosomes (purple).
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Cerdanyola del Vallès, 22 June 2020 Squamous cell carcinoma (SCC) is the second most common form of skin cancer. It is caused by abnormal growth of squamous cells in the epidermis and accounts for 20-25% of all skin cancers in Spain. Now, a team of researchers from Institut d'Investigació i Innovació Parc Taulí (I3PT) and the ALBA Synchrotron has shown that using tricine as an adjuvant to cisplatin-based topical chemotherapy can boost apoptosis of cancerous cells. The results, published in PLOS ONE, point to a new therapeutic approach that would also reduce adverse effects of cisplatin.
In healthy individuals, squamous cells – flat cells also known as keratinocytes – shed continuously to make way for fresh cells. However, the cumulative exposure to ultraviolet radiation can produce DNA damage and trigger anomalous behaviors. Most of the time, lesions arise in sun-exposed areas of the body like the face and the hands of elderly people, although it’s also a common cancer in people who use tanning salons. And while this cancer is mostly curable, especially if detected early, non-treated lesions can grow and invade other layers of the skin and even other parts of the body. If this happens, SCC can evolve into a deadly cancer.
Taulí and ALBA, a fruitful collaboration against cancer
The story behind this research is that of a collaboration between two nearby research institutions: Hospital Parc Taulí, that serves a population of around 400,000 people in the Barcelona area, and its research institute I3PT, and the ALBA Synchrotron, a major research infrastructure in Europe. “The collaboration between research centers such as Taulí and ALBA is a key piece in the advancement of biomedical research through the use of synchrotron light techniques,” says Manel Sabés, a researcher with links to both ALBA and I3PT.
Experiments were performed a couple of years ago while Silvia Gil, corresponding author of this work and PI of the neuro-oncology research group at I3PT, was making a 6-month postdoctoral stay at ALBA, working together with its scientists Christina Kamma-Lorger and Eduardo Solano, as well as MISTRAL beamline scientists Javier Conesa and Ana J. Pérez.
MISTRAL is a soft X-ray microscope beamline that allows a 3D view of cells in their natural state. Thanks to this cutting-edge technique, which is only available in three other synchrotron light facilities around the world, biomedical researchers can perform a tomogram of a cell with a million times better resolution than a conventional CT scan.
The results of these 3D images show changes in the cell structure that lead to apoptosis. Researchers have also evaluated the penetration of the treatment through the cell membranes, which can only be observed at the nanometric scale provided by MISTRAL.
Reducing the toxicity of topical treatments
Topical medications are used for superficial tumors as well as precancerous conditions, and can also provide an effective treatment for local invasive cancers when surgery is not feasible.
For a long time, 5-fluorouracil has been a standard topical treatment for cutaneous SCC. This drug prevents the reproduction of the cell and the synthesis of certain proteins, which cause early apoptosis of the affected cells. However, an effective treatment requires pretty high concentrations and 2-12 weeks lasting treatments that induce important secondary effects.
This has motivated searches for safer drugs such as cisplatin-based chemotherapy, which produces a stronger apoptotic rate with lower concentrations and shorter treatment periods. However, it also causes significant adverse effects such as nausea as well as hearing and kidney disorders or asthenia.
Now, “we have found that using tricine as an adjuvant can both increase the effectiveness of the treatment and lower the toxicity. And, last but not least, this would be an affordable treatment that combines two existing commercial drugs,” explains Sílvia Gil, principal researcher.
Tricine, a powerful cisplatin enhancer
In this study, researchers have assessed in vitro, on human squamous cutaneous carcinoma cells, the effects of several treatments using small concentrations of cisplatin alone, as well as cisplatin combined with two different adjuvants: tricine and gold nanoparticles.
When gold nanoparticles were combined with cisplatin, a similar decrease of the living cell population was found with respect to cisplatin administered alone, but causing slightly larger cell damage. Therefore, these results rule out gold nanoparticles as an advantageous adjuvant for cisplatin skin chemotherapy under the experimental conditions.
On the contrary, adding tricine to the smallest cisplatin concentration led to a significant decrease of the cell population and simultaneously increased apoptotic death cell rate. Thus, this combination enhances the effectiveness of the treatment while minimizing cell damage and related adverse effects.
“The results prove that very low concentrations of cisplatin can be used in chemotherapy treatments of squamous cell carcinomas, and that using tricine as an adjuvant can even up the effects of a fourfold cisplatin dose,” explains Christina Kamma-Lorger, an expert in skin cancer at ALBA and one of the lead scientists of this project.
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The image above shows the percentage of living cells after treatment. The largest decrease was found when tricine was used as an adjuvant, while gold particles only produce a small improvement with respect to free cisplatin. Results are expressed as mean percentages (± standard deviations).
Referencias:
Multiparametric Analysis of the Effectiveness of Cisplatin on Cutaneous Squamous Carcinoma Cells Using Two Different Types of Adjuvants. S.Gil, E. Solano, F, Martínez-Trucharte, J. Martínez-Esaín, A. J Pérez-Berná, J.J. Conesa, C.Kamma-Lorger, M.Alsina, M. Sabés. PLoS One 2020; 15(3). DOI: 10.1371/journal.pone.0230022
A comparative study of the effectiveness of cisplatin and 5-fluorouracil on cutaneous squamous human carcinoma cell line: Potential chemotherapy alternative to surgery. S. Gil, M. Yébenes, J. Luelmo, M. Alsina, M. Sabés. Dermatol Ther. 2016; 29: 341–344. DOI: 10.1111/dth.12373.
