New understanding of resistance to chemotherapy and cancer relapse

In chemotherapy treatment, anti-cancer drugs are used to kill cancer cells. These drugs trigger a process of programmed cell death (apoptosis) and also impair the function of mitochondria; which are the parts of the cell that regulate the cell's energy production and are essential in maintaining the balance of water and ions, which include substances such as minerals and salts, in the cell (osmotic homeostasis). While apoptosis and impairment of mitochondrial function both lead to cell death, some cancer cells manage to evade both processes to survive the chemotherapy treatment. The study by the RCSI team is the first to reveal the mechanisms by how these cells survive.

The research has shown that chemotherapy resistance is due to a difference in the metabolism which exists in cancer cells compared to normal human cells. In addition to producing energy in the mitochondria, cancer cells can also energy by using glucose in a process known as glycolysis. While it was previously known that this process of glycolysis can restore energy levels in cancer cells being targeted by chemotherapy, this study has revealed that glycolysis also helps to restore mitochondrial function which means that the cancer cells may continue to function following the treatment.

Dr Heinrich Huber, Senior Lecturer at the Department of Physiology and Medical Physics, RCSI commented: "Our findings show that when cancer cells are exposed to elevated glucose levels, mitochondrial function can be restored and osmotic homeostasis can be maintained which contributes to resistance to chemotherapy. Therefore, we have found that in order for cancer treatments to be effective, they must target the cancer cell's ability to produce energy by using glucose within its fluids as well as destroying the mitochondria."

"It is also important that glucose levels in patients are monitored because this can be a factor in resistance to treatment. We hope that our research may inform new potential treatments for cancer." Dr Huber concluded.

Cancer is the second leading cause of death in Ireland with over 16,000 new cases of cancer are diagnosed each year.⁽¹⁾ Current cancer treatments are limited in their effectiveness with poor 5 year survival rates of just 55% reported. ⁽²⁾ Globally, approximately 12.7 million cancers are diagnosed annually (excluding non-melanoma skin cancers and other non-invasive cancers) and 7.6 million people die of cancer worldwide.⁽³⁾

Dr Huber was joint lead author of the study with Dr Heiko Dussmann, in collaboration with colleagues Dr Seán Kilbride, Dr Markus Rehm and senior author, Professor Jochen HM Prehn, at the Centre of Human Proteomics and Medical Systems Biology, Department of Physiology and Medical Physics, RCSI.

The research was conducted using a systems biology study that combined computational modelling and live cell microscopy.

The research was published in the scientific journal Molecular Systems Biology⁽⁴⁾ and the research team was funded by Science Foundation Ireland, the National Biophotonics and Imaging Platform, the EU Framework Programme 7 and the Health Research Board.

Notes:

(1) National Cancer Registry Ireland 2007 figure for newly diagnosed cancer cases

(2) National Cancer Registry Ireland reports 55.4% five-year survival rates for all cancers excluding non-melanoma skin cancer from 2005-2008

(3) Jemal, A; Bray, F, Center, MM, Ferlay, J, Ward, E, Forman, D. "Global cancer statistics." CA: a cancer journal for clinicians. 60:2

(4) Huber HJ, Dussmann H, Kilbride S M, Rehm M, Prehn JHM. Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release. Molecular Systems Biology. 7:470