EXPLORATION OF METFORMIN EFFECT OVER OXALIPLATIN ANTINEOPLASIC PROPERTIES IN MKN45, KATOIII AND HS746T GASTRIC CANCER CELL LINES IN VITRO AND OVER OXALIPLATIN INDUCED RAT PAINFUL SENSORY NEUROPATHY IN VIVO.
Chemotherapy induced peripheral neuropathy (CIPN) is a pathological condition presented as a dose-limiting adverse effect of certain cancer treatments that affects long term quality of life by induction of transient or permanent disability. Chemotherapeutics induce axonal degeneration (AD), intraepi...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/227003 |
| Acceso en línea: | https://hdl.handle.net/10533/227003 |
| Access Level: | acceso abierto |
| Palabra clave: | Ciencias Naturales Otras Ciencias Naturales |
| Sumario: | Chemotherapy induced peripheral neuropathy (CIPN) is a pathological condition presented as a dose-limiting adverse effect of certain cancer treatments that affects long term quality of life by induction of transient or permanent disability. Chemotherapeutics induce axonal degeneration (AD), intraepidermal nerve fibers degeneration (IENFD) and glial activation at the central sensory circuits. There, chemotherapy induced hyperexcitability and ectopic discharges have been associated with sensory symptoms such as dysesthesia, paraesthesia and allodynia. Those CIPN symptoms often lead to an early suspension of chemotherapy that significantly reduces life expectancy. Unfortunately, there are no effective treatments for CIPN. This thesis explores proof of concepts to suggest the anti-diabetic drug metformin for further research as an experimental target to develop a potential treatment for CIPN. The effect of metformin was assayed in a model of oxaliplatin induced peripheral neuropathy (OIPN), which is characterized by oxaliplatin toxicity over dorsal root ganglia (DRG) sensory neurons. Considering that chemotherapy toxicity occurs in the context of an anticancer treatment, we first evaluated the role of metformin over the antineoplasic effect of oxaliplatin. To this goal, we determined cell survival of three different gastric cell lines (MKN45, HS746T and KatoIII cells) under several concentrations of oxaliplatin and metformin cotreatment. In all studied gastric cancer cell lines, we found that the significant reduction of cell survival induced by oxaliplatin was unaffected by metformin cotreatment. This result suggests that metformin does not interfere with the antineoplasic effect of oxaliplatin. Then, we explored the effect of metformin over oxaliplatin induced toxicity over sensory neurons at DRG and sensory function. To this goal, metformin was administered to rats undergoing oxaliplatin induced peripheral neuropathy (OIPN) and histological markers of degeneration along central and peripheral branches of DRG were determined after sensory function performance testing along the time of OIPN progression. Specifically, degeneration of peptidergic and non peptidergic neurons was explored along the peripheral and central branches of L4, L5 and L6 sensory neurons at IENF, sciatic nerve, dorsal root ganglia (soma) and spinal cord terminals. Additionally, activation of astrocytes was explored also at the spinal cord. In this context, metformin significantly inhibited oxaliplatin induced degeneration of IENF and activation of astrocytes in the spinal cord. Furthermore, oxaliplatin treatment induced a significant decrease threshold of the withdrawal response for mechanical stimulus and in the withdrawal latency response to heat stimulus. Additionally, oxaliplatin treatment also induced a significant increase in the withdrawal response duration to cold. Surprisingly, metformin cotreatment to rats treated with oxaliplatin maintained the sensory function performance at control levels. Altogether, these results suggest that metformin protects against OIPN. Finally, white blood cells, glycaemia and weight levels were periodically assayed to evaluate the effects of our treatments over relevant physiological variables. The levels of all these variables remained in physiological ranges under all the treatments along the study. Those results suggest that our experimental model is resolutive in a physiological framework in rats. Considering this, the administration regime, dosage and outcomes presented in this thesis could be potentially extrapolated to the clinical context. In conclusion, this group of findings provide a fundamental set of proof of concepts to a potential treatment against CIPN based on metformin administration. However, further research is needed to determine the cellular and molecular mechanism behind the ubiquitous protective effect of metformin against the toxicity of oxaliplatin over pain fibers and consequent maintenance of the sensory function in the context of OIPN. Additionally, large scale studies are needed to extrapolate these findings to the context of CIPN treatment in humans. |
|---|