UC Irvine-led study shows common diabetes drug may be effective against bladder cancer
Higher concentration in urine found to be more therapeutic than in the bloodstream
February 26, 2016
The accumulation of a high concentration of the common diabetes drug metformin in urine shows promise in inhibiting the growth of bladder cancer tumors, according to findings published today in Molecular Cancer Therapeutics, a journal of the American Association of Cancer Research.
Led by Xiaolin Zi, PhD, a professor of urology in the University of California, Irvine School of Medicine, and colleagues from UC Irvine, New York University and McGill University, the study examined whether metformin treatment in mouse models of bladder cancer demonstrated anti-tumor activity.
“Bladder cancer is a major public health challenge, as the treatment cost per patient from diagnosis to death is among the highest of all cancers in the U.S.,” said Zi. “Developing a safe, convenient, low-cost drug that can be taken orally for the prevention and treatment of disease recurrence is a clear priority in urologic oncology.”
Zi’s group concluded that the accumulated concentration of orally administered metformin in urine is about 240 fold higher than in the bloodstream. This elevated concentration exposes bladder cancer tumors to a therapeutically effective dosage of metformin not attainable for other types of cancer, which are exposed to metformin via the bloodstream. They found that the high concentration accumulated in the mouse bladder was sufficient to interfere with the mTOR signaling pathway, which is associated with maintaining bladder cancer cell metabolism and function.
“We believe our findings justify carefully designed clinical trials to determine whether high concentration oral doses of metformin in early bladder cancer might be effective, despite disappointing clinical trials for other cancers in which the drug exposure levels in the bloodstream were far lower,” Zi said.
Superficial bladder cancer is the most common cancer of the bladder and urinary tract. Despite current treatments such as transurethral resection and intravesicular BCG or mitomycin C, it is associated with high risk of recurrence and/or progression to invasive and metastatic disease. Many of the current chemotherapeutic regimens carry significant side effects and toxicities.
Zi said there has been a paucity of new medications for the treatment of superficial bladder cancer. Valrubicin in 1998 was the last intravesical agent to be approved by the FDA. This research presents the possibility of using a safe, well-tolerated, oral medication to decrease bladder tumor recurrence and progression with minimal cost (generic, under 30 cents/pill). He said the next step is a collaboration with Dr. Edward Uchio, the director of urological oncology and clinical research for UCI Health and associate professor of urology in the UC Irvine School of Medicine, on planning a clinical trial of metformin for superficial bladder cancer patients.
About 74,000 new cases of bladder cancer are reported annually in the U.S. The American Cancer Society estimates that 16,000 Americans will die from the disease this year.
The study, “High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin,” was conducted by Zi and colleagues Zhongbo Liu, Noriko N. Yokoyama, Chris A. Blair, Xuesen Li, Daina Avizonis, Xue-Ru Wu, Edward Uchio, Ramy Youssef, Michael McClelland, and Michael Pollak.
It was supported in part by National Institutes of Health awards 5R01CA122558-05 and 1R21CA152804-01A1 and an award from the Terry Fox Cancer Research Institute.
UCI Health comprises the clinical, medical education and research enterprises of the University of California, Irvine. Patients can access UCI Health at physician offices throughout Orange County and at its main campus, UC Irvine Medical Center in Orange, Calif., a 411-bed acute care hospital that provides tertiary and quaternary care, ambulatory and specialty medical clinics, behavioral health and rehabilitation. U.S. News & World Report has listed it among America’s Best Hospitals for 15 consecutive years. UC Irvine Medical Center features Orange County’s only National Cancer Institute-designated comprehensive cancer center, high-risk perinatal/neonatal program, Level I trauma center and Level II pediatric trauma center, and is the primary teaching hospital for UC Irvine School of Medicine. UCI Health serves a region of more than 3 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us on Facebook and Twitter.
About the University of California, Irvine: Currently celebrating its 50th anniversary, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $4.8 billion annually to the local economy. For more on UCI, visit www.uci.edu.