EVALUATION OF SOLAMARGINE AS A THERAPEUTIC IN BLADDER CANCER

PEE HAI NING

Publication

EVALUATION OF SOLAMARGINE AS A THERAPEUTIC IN BLADDER CANCER

PEE HAI NING

Abstract

Globally, bladder cancer ranks 11th in terms of incidence and ranks 14th in terms of mortality rate amongst all cancers. In Singapore, bladder cancer is the 12th most common cancer. However, even though bladder cancer is neither as common or deadly, it has the highest lifetime treatment cost per patient. This is due to the cancer’s high incidence, recurrence and survival rates. At present, the common therapies for bladder cancer include, transurethral resection or cystectomy, intravesical Bacillus Calmette-Guérin (BCG) and intravesical chemotherapy. These therapies are used in combination, but treatment response remains suboptimal with regards to side effects and the prevention of recurrence and progression. Hence, the purpose of this thesis is to explore new therapeutics with the objective of improving bladder cancer treatment outcomes through the complete extermination of bladder cancer cells. In order to achieve this, six compounds, solamargine (SOM), solasonine (SON), solasodine (SOD), metformin (MET), propranolol (PRO) and captopril (CAP) together with the standard chemotherapy drug, mitomycin c (MMC) were evaluated for cytotoxicity against various bladder cancer cell lines. Amongst all the compounds, SOM was found to be rapid acting, most potent with some selectivity. MET was found to have low potency and was selectively potent to bladder cancer cells. To further improve the efficacy of the drugs, drug combination treatments were explored with MMC, MET and SOM. Significantly, synergism was observed for SOM and MET drug combination against UMUC-3 cells while MMC and SOM drug combination had limited synergism against bladder cancer cells. MMC and MET drug combination was observed to be antagonistic against bladder cancer cells and hence, healthcare professionals should be cautioned against the co-administration of both drugs. Lastly, microarray was performed to identify pathways that were affected by SOM treatment. Tumour necrosis factor (TNF) signalling pathway, mitogen-activated protein kinase (MAPK) signalling pathway and nuclear factor-kappa B (NF-κB) signalling pathway were found to be enriched after SOM treatment and it is hypothesised that the sustained activation of Jun N-terminal kinase (JNK) pathway led to apoptosis and previous studies have shown that concurrent activation of NF-κB signalling pathway reduced the pro-apoptotic effect of JNK activation, suggesting that the treatment of SOM together with a NF-κB inhibitor could increase the cytotoxicity of SOM.