Bladder cancer is one of the most prevalent cancers in the urinary tract and is ranked 9th for malignancies of all malignancies in the world. In men, bladder cancer is ranked 7th for most prevalent malignancy with an incidence of 10.1 per 1,000,000 population, while in women it is ranked 17th with an incidence of 2.5 per 1,000,000 population.
About two-thirds of bladder cancer cases are non-muscle invasive bladder cancer (NMIBC) and about one-third of them are muscle-invasive bladder cancer (MIBC). Currently, the standard treatment for bladder cancer is transurethral resection of bladder tumor (TURB), followed by intravesical instillation in NMIBC cases and radical cystectomy or chemotherapy using radiotherapy in MIBC cases. However, the progression and recurrence of bladder cancer is still common.
Some bladder cancer cells can be resistant to chemotherapy resulting in recurrence and / or progression to more severe cancer. For example, bladder cancer cells that are initially sensitive to cisplatin-based combination chemotherapy may become resistant to these chemotherapy agents. Cisplatin-based chemotherapy is commonly used for MIBC, in combination with other chemotherapeutic agents. However, the success rate of combination chemotherapy is still low.
The response rate for MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) is 46% while GC (Gemcitabine and Cisplatin) was 49%. The MVAC and GC survival rates are 14.8 and 13.8 months, respectively. This condition indicates the lack of efficacy of the available standard chemotherapy. Furthermore, the side effects of each of these chemotherapy are also factors to consider.
Metformin is a Type II Diabetes Mellitus (DM) drug. Metformin has the ability to reduce the incidence and prevalence of various types of cancer in animal models. Metformin is also able to reduce the progression and recurrence of various types of cancer in animal models. In particular, metformin is also able to reduce the incidence of bladder cancer in diabetic patients. Moreover, metformin can also improve recurrence-free survival and bladder cancer-specific survival in diabetic patients after radical cystectomy. At the cellular level, metformin is also capable of inducing apoptosis and decreasing the proliferation of bladder cancer cells.
The cytotoxicity test is a preliminary test to determine the toxicity potential of the compound against cancer cells. Cytotoxicity test in this study using the microculture tetrazolium salt (MTT) assay method proved that metformin was able to reduce the proliferation of bladder cancer cells. Several studies have shown that metformin has anti-bladder cancer effects and is effective in certain types of cancer.
Cisplatin exposure to bladder cancer cells also had a similar effect as metformin’s effect. The greater and longer exposure to cisplatin, the lower the bladder cancer cell proliferation. Furthermore, the dose of metformin needed to achieve 50% cell viability (IC 50 ) is much greater than the cisplatin dose.
This study observed the bladder cancer cells after exposure to metformin or cisplatin either as a single agent or in combination with different doses. This is very important because in cytotoxicity tests, it is not known whether cell death is caused by apoptosis or necrosis. The apoptosis test in this study consisted of five groups, namely one control group (without treatment) and five treatment groups were exposed to IC 50 metformin , IC 50 cisplatin, a combination of ¼ IC 50 (metformin and cisplatin), ½ IC 50 (metformin and cisplatin) , and IC 50 (metformin and cisplatin) obtained from prior cytotoxicity tests.
In this study it was proven that metformin alone was not able to significantly increase the apoptosis of bladder cancer cells compared to the control group. In contrast, cisplatin administration significantly increased the apoptosis of bladder cancer cells compared to the control group. These results refute the previous theory that metformin can increase the apoptosis of bladder cancer cells. The addition of the combined dose of metformin + cisplatin showed a significant increase of apoptosis, known from the Post Hoc Analysis in which the combination metformin + cisplatin dose ¼ IC 50 group initially did not differ significantly from the control group, becoming significantly different when the dose was increased to ½ IC 50 and IC 50.
IC 50 Metformin dose cannot increase apoptosis of bladder cancer cells. Meanwhile, IC 50 cisplatin dose can significantly increase apoptosis of bladder cancer cells. The combination of metformin and cisplatin can also increase apoptosis of bladder cancer cells. The increase in the dose of the combination of metformin and cisplatin was in line with the increase in the apoptosis of the bladder cancer cells. (*)
Authors: Arifai Lumbangaol, Lukman Hakim, Doddy M. Soebadi, Tarmono Djojodimedjo
Details of this research available at:
http://juri.urologi.or.id/juri/article/view/600
