Researchers find Indian plant used for centuries as a malaria treatment may eradicate cancer cells
Neem the legendary medicinal tree of India has been used for centuries to treat numerous diseases and illnesses may play a part in anti-cancer therapies according to researchers from Georgia Regents University Cancer Center.
Dr. Ahmed Chadli, PhD, researcher and assistant professor, Molecular Chaperone Program, Georgia Health Sciences University, Department of Medicine and Cardiology and senior author of study remarked cancer cells typically avoid death by hijacking molecular chaperones that guide and protect the proteins that ensure normal cellular function and then tricking them into helping mutated versions of those proteins stay alive.
Drug development has focused on the chaperone Hsp90 (heat shock protein 90) because it plays a key role in assisting mutated proteins, making it an attractive cancer drug target. Cancerous cells overexpress a number of proteins, including growth factor receptors, such as EGFR, Hsp90 stabilizes various growth factor receptors and some signaling molecules.
However, the clinical efficacy of Hsp90 inhibitors has been disappointing. Most current small molecules targeting Hsp90 have inadvertently resulted in the expression of proteins that protect cancer cells from programmed cell death and compromise the Hsp90 inhibitors in the clinic.
In this study Chaitanya Patwardhan, graduate research assistant in Dr. Chadli's lab and PhD candidate Georgia Health Sciences University had found the compound gedunin in the Neem tree, attacks a co-chaperone, or helper protein, of Hsp90 called p23.
The researchers write “Functional analysis shows that gedunin inhibits p23 chaperoning activity, blocks its cellular interaction with Hsp90 and interferes with p23-mediated gene regulation. Cell treatment with gedunin leads to cancer cell death by apoptosis through inactivation of p23 and activation of caspase 7, which cleaves p23 at the C-terminus. These results provide important insight into the molecular mechanism of action of this promising lead compound.
Dr. Chadli explains "This compound binds directly to p23, leading to inactivation of the Hsp90 machine, without production of anti-apoptotic proteins, thus killing cancer cells.” "The idea here is that this will open a door for new ways of targeting Hsp90 by targeting its helper proteins, which may be used in combination with established Hsp90 inhibitors that are ongoing clinical trials. In the future, this research could have applications in drug development for hormone-dependent cancers, including breast, prostate and endometrial cancers."
“Gedunin is a promising lead compound to develop anti-cancer therapeutics,” write the researchers.
Dr. Samir N. Khleif, MD, Chief of the National Cancer Institute’s Cancer Vaccine Section, Director of the GRU Cancer Center stated "One of the major areas of scientific emphasis of the GRU Cancer Center is to develop therapeutic approaches to cancer targeting specific molecules within the cancer cell, including chaperones.” "This finding is an important piece of the puzzle, bringing us closer to our goal of helping patients with cancer."
The study appears in the Journal of Biological Chemistry's Paper of the Week.
More information on neem is available at the Neem Foundation.