Cutts - Cellular responses to anticancer drugs

The anticancer drugs doxorubicin (an "anthracycline") and mitoxantrone (an "anthracenedione") are widely used in cancer chemotherapy, and are classified as inhibitors of topoisomerase II. We strive to develop new therapeutic strategies for cancer treatment by understanding the mechanism of action of these currently used anticancer drugs, and building on this information to restrict their killing properties to cancerous cell types. In this way, the toxic side effects of these drugs can be minimised.

It is now well established that anthracyclines such as doxorubicin can bind covalently to DNA to form DNA adducts when activated by the simple molecule formaldehyde. We can activate doxorubicin to bind covalently to DNA in this manner by supplementing with low toxicity formaldehyde-releasing prodrugs. These lesions provide a more lethal death-inducing signal in cells than damage which occurs in the absence of formaldehyde (ie topoisomerase II-mediated damage). The combination of anthracyclines with formaldehyde-releasing agents may prove clinically beneficial.

Research areas

A new mechanism to prevent anthracycline-induced cardiotoxicity while maintaining anticancer activity

Cardiotoxicity is the most serious adverse event associated with anthracyclines which have been widely used in cancer therapy for at least four decades and have led to increased cancer cure rates. A consequence is an increased population with a survival expectancy long enough to carry a lifetime risk for anthracycline-related cardiotoxicity. The potential for cardiovascular problems in many paediatric patients and adults treated with anthracyclines will become apparent in coming years. This cardiotoxicity risk and the requirement for surveillance or intervention increase the cost of health care and compromise quality of life. Since the anthracyclines will continue to be widely used, cardiotoxicity preventative strategies are urgently needed.

Although doxorubicin is primarily considered a TOP2 poison, under certain conditions it can also bind covalently to DNA. This mechanistic switch is controlled by cellular formaldehyde availability. Supplementation of cellular formaldehyde levels using esterase-activated formaldehyde prodrugs switches the mechanism of action of doxorubicin from TOP2 poisoning to covalent DNA adduct formation.

We have observed that the formaldehyde-releasing prodrug AN-7 augments anthracycline anticancer potential while simultaneously reducing cardiotoxicity. We are seeking to identify the mechanism by which formaldehyde-activated anthracyclines protect cardiac cells from undergoing cell death. Although the anthracycline cardiotoxicity problem has been well known for decades, anthracycline covalent lesions have never been examined in the context of this problem.

Development of tumour targeted nanoparticles

Anthracycline and anthracenedione anticancer agent primarily induce topoisomerase II poisoning which leads to accumulation of lethal double-strand DNA breaks in cancer cells. The objective is to improve the effectiveness of these widely used anticancer drugs using targeted nanoparticle therapy. Our research addresses the serious side-effects of the anthracycline drugs, also potentially enabling lower doses to be employed. One aspect of this study encapsulates anthracyclines and anthracenediones in the nanoparticles for tumour-specific drug delivery.

We also endeavour to increase the anticancer potency of anthracyclines by developing nanoparticles for localised formaldehyde release in the tumour environment. This requires the development of a carrier system to protect formaldehyde-releasing prodrugs from non-specific esterase-mediated hydrolysis, allowing them to biodistribute intact to tumour tissue. A dramatic tumour growth inhibitory response to our combination treatment in a 'triple negative' MDA-MB-231 breast tumour model indicates that such a treatment strategy could be particularly useful for such tumours in the clinic.

This study requires us to take a multidisciplinary approach in our research which incorporates expertise in a range of diverse areas including drug-DNA interactions, cell biology, nanotechnology, biomolecular surface analysis, medicinal chemistry and preclinical drug evaluation.

Meet the team

Group members

Dr Suzanne Cutts GroupGroup leader

Dr Suzanne Cutts

Emeritus professor

Professor Don Phillips

Research assistant

Tina Robinson

PhD students

Alison Cheong
Ruqaya Maliki
Sean McGrath
Wil Gardner

Publications

See a full list of publications [external link], ResearchGate [external link] or view Dr Suzanne Cutts's profile.