Areas of solid tumors that have limited access to oxygen, a condition called hypoxia, are highly resilient against chemo and radiation therapy. For years, scientists have wondered why the tumor suppressor protein p53 is also ineffective against hypoxic cells of these tumors. Lack of oxygen, or hypoxia, is a biological stressor that occurs under various conditions such as wound healing and stroke. To rescue the tissue, the body has innate mechanisms that “kick in” to make the cells of the hypoxic tissue more resistant and assist in tissue repair. One such mechanism is the expression of a protein called Hypoxia Induction Factor (HIF), which controls several processes such as glucose uptake, growth of blood vessels and cell proliferation. Despite its beneficial role in some diseases, HIF has also been found to be an important contributor towards cancer. Many studies have tried to elucidate the relationship between hypoxia, HIF and p53, without clear conclusions.
Now, a study reports the discovery of a mechanism that renders p53 ineffective against hypoxic cancer cells and in fact promotes their survival. These results may have important implications for future therapies. A team of scientists led by Dr. Rajan Gogna, of the Champalimaud Centre for the Unknown in Lisbon, Portugal, have identified the source of the tumor’s resistance to p53. To investigate this question, the multi-institutional team, which included groups in Portugal, the United States, the United Kingdom, India and Japan, carefully measured and simulated physiological hypoxia in tissue from humans and investigated the molecular changes that were induced in that tissue. Using this approach, the team discovered that lack of oxygen alters the shape of p53, thereby inhibiting its ability to perform its role. Their showed that when p53 is subjected to hypoxic conditions, this protein changes its conformation becoming unable to bind to the DNA.
This realization clarified why p53 was not effective under hypoxia, but then, the team made a surprising discovery — hypoxic cancer cells were in fact producing p53 in large quantities! This unexpected result led the team to investigate further this reason. Their analysis revealed that the shape p53 assumes under hypoxic conditions actually leads it to bind to HIF and stabilize it, thereby facilitating HIF’s pro-survival action in cancer cells. According to Dr. Gogna, these key findings may have important clinical consequences: observing the expression of p53 within tumors could potentially indicate how aggressive is the tumor. This research has special focus on pancreatic cancer, as hypoxia-assisted resistance to chemotherapy is one of the most frustrating menaces associated with this malignancy. In addition, this new molecular pathway is important for cancer as well as for other diseases that involve presence of chronic hypoxia which include, among others, inflammatory bowel disease, rheumatoid arthritis, epilepsy and cardiac heart failure.
Dr Zhu Guangyu, Associate Professor of Department of Chemistry, City University of Hong Kong (CityU) and his research team have recently developed phorbiplatin, an anti-cancer prodrug that can be controllably activated by red light. With its unique “on-site” activation characteristic, it will effectively kill cancer cells and minimize damage to normal tissues. Phorbiplatin is a platinum(IV) anti-cancer prodrug, meaning is a compound that will only be pharmacologically active after processing inside the body. Phorbiplatin is shown to be inert in the dark but can be activated under low-power red-light irradiation (650 nm, 7 mW/cm2). Under short-period irradiation with low intensity of red light and without any external catalyst, phorbiplatin is reduced to oxaliplatin, a first-line clinical chemotherapeutic drug, as well as pyropheophorbide A (PPA). Both substances are effective in killing tumor cells. Previously, researchers utilized ultraviolet light to activate small-molecule platinum anti-tumor drugs. However, UV light has poor penetration depth and can also damage cells.
Therefore related experiments have not yet been conducted in vivo. On the contrary, red light does not harm normal cells. And it possesses higher penetration depth through the skin to reach the subcutaneous tumor. The team functionlized oxaliplatin with PPA, which is a photosensitizer in photodynamic therapy and highly sensitive to red light. Under irradiation with low intensity of red light, PPA acts as a “photo-induced redox relay” to transfer electrons from reducing agents to the platinum(IV) center to facilitate the reduction process, and as a result, releasing oxaliplatin. The team also examined the cytotoxicity of phorbiplatin to different tumor cells. They found that platinum-sensitive (A2780) human ovarian cancer cells treated with phorbiplatin under red light irradiation showed high fractions of dead (68.0%) cells. Compared with oxaliplatin, phorbiplatin displayed a remarkable ability to kill human breast cancer cells (MCF-7) up to a 1,700-fold better, and cisplatin-resistant ovary cancer cells (A2780cisR) up to 950 times better.
Moreover, phorbiplatin with irradiation significantly inhibited tumor growth in mice, with 67% reduction in tumor volume and 62% reduction in tumor weight compared with mice treated with oxaliplatin, PPA, and even a mixture of oxaliplatin and PPA. And for the mice treated with phorbiplatin under irradiation, their organs like heart, liver, spleen, lung and kidney were in good conditions, further confirming the safety of phorbiplatin. This controllable activation property and superior anti-tumor activity of phorbiplatin significantly contribute to the development of photoactivatable anti-cancer prodrugs, especially platinum(IV) prodrugs that can be activated by red light, to reduce the adverse effects and conquer drug resistance of traditional platinum chemotherapy. The team will work on pre-clinical study and conduct more efficacy and toxicity assays. They believe that due to the improved molecular structure, it is easier for phorbiplatin to enter the tumor and accumulate, triggering DNA damage and eventually kill the cancer.
- Edited by Dr. Gianfranceco Cormaci, PhD, specialist in Clinical Biochemistry.
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