A seemingly ordinary-looking plant that grows between the pavement cracks in Singapore, Oldenlandia corymbosa (O. corymbosa), also known as the Old World Diamond Flower, could be a valuable natural resource in the fight against cancer.
Recently, a team of scientists from the NTU School of Biological Sciences (SBS), led by Associate Professor Marek Mutwil, have shown that ursolic acid present in extracts from O. corymbosa is active against breast cancer cells. In a paper published in the Journal of Integrative Plant Biology, the team also succeeded in assembling a high-quality genome of O. corymbosa, and uncovered two genes involved in the biosynthesis of ursolic acid – thus paving the way for developing this valuable compound.
A specimen of Oldenlandia corymbosa
Plants constitute a significant source of anti-cancer drugs approved by government health agencies. The advantage of using natural products over classical chemotherapeutics is their effect on multiple signalling pathways and molecular targets. Plant-derived drugs induce apoptosis (cell death), inhibit proliferation (cell growth), and suppress metastasis (spread of cancer cells from original site to other parts of the body), while causing few adverse effects. In contrast, classical synthetic chemotherapeutics are often single-targeted, and therefore more prone to drug resistance. However, a recurring problem with medicinal herb extracts is that neither the active agents nor their modes of action are well-characterized. Moreover, the composition of the formulas is complex and not standardized, thus not fulfilling guidelines for drug approval.
Plants synthesize a vast array of secondary metabolites as part of their defense against pathogens or when subjected to stressful conditions and are thus a natural resource for pharmaceuticals. This has been acknowledged for thousands of years in traditional Chinese and Ayurvedic medicine, and scientists worldwide have been toiling away in the laboratories in efforts to mine this potential for novel antibacterial or anti-cancer drugs.
However, most studies are constrained to testing the plants for activities and identifying candidates for the active metabolites without knowing the mode of action or the enzyme-coding genes. The major reason for this limitation is that the genomes of medicinal plants are usually not sequenced. Even if the genome sequence is known, the successful identification of which enzyme-coding genes synthesize a given metabolite requires advanced experimental and computational methods applied to comprehensive datasets.
Left to right: Dr Daniela Mutwil and Dr Irene Julca
History of Oldenlandia corymbosa in medicine
O.corymbosa – an unassuming plant with small white flowers – is a commonly used herb in China and India for health benefits and wellbeing. Its leaves are used to treat multiple ailments, such as sore eyes, fever, and jaundice. There are reports on anti-cancer activities of O. corymbosa against skin cancer, leukaemia, and liver cancer cells. It is commonly found as the main ingredient in traditional Chinese herbal formulations such as the popular antitumor Peh-Hue-Juwa-Chi-Cao medicine together with Oldenlandia diffusa and other herbs. Until these studies, O. corymbosa was long considered as inferior when compared to the more widely studied O. diffusa, which has been used for the treatment of inflammation-linked diseases, such as hepatitis, appendicitis, and urethritis in traditional Chinese medicine. While both O. diffusa and O. corymbosa have documented medicinal properties, the identity, biosynthesis, and mode of action of the active metabolites are still largely unknown.
As natural products are becoming increasingly prominent in cancer therapy, the team set out to identify the main anti-cancer metabolites and their biosynthetic pathways of the Oldenlandia genus. To this end, they collected 11 plants comprising O. corymbosa, O. biflora, and O. tenelliflora, and showed that O. corymbosa had the most potent activity against several breast cancer cell lines.
To enable molecular studies of O. corymbosa and to identify the biosynthetic pathways of the anti-tumor metabolites, the team generated a high-quality genome sequence of O. corymbosa. They then set out to identify the main anti-cancer metabolites and their biosynthetic pathways of the Oldenlandia genus.
Dr Daniela Mutwil working on Oldenlandia corymbosa
Ursolic acid, the main character in stopping cancer cells
Ursolic acid has been reported to possess a multi-pronged anti-cancer activity. The researchers used activity-guided fractionation to confirm that ursolic acid is indeed the main metabolite responsible for anti-cancer activity in O.corymbosa, with a minor contribution of other compounds. Ursolic acid’s anti-cancer activity is demonstrated in causing a mitotic catastrophe – cell death that occurs resulting from abnormal or disrupted cell division – in the breast cancer cell lines, destroying them.
Identifying the human protein targets of ursolic acid
While ursolic acid is known to possess a wide range of anti-cancer activities, the direct protein binding partner of ursolic acid is unknown. By harnessing a combination of Cellular Thermal Shift Assay (CETSA) – a method to identify protein targets of drugs – and reverse docking, the team succeeded in identifying six high-confidence human protein targets of ursolic acid, three of which (HIBCH, DECR1, RPLP1) have been implicated in cancer.
Significance of the team’s findings
By presenting the high-quality genome of the Oldenlandia genus and characterizing the mode of action of the main active compound – ursolic acid, the team anticipates that the genome will be valuable for scientists working on the medicinal properties of the Oldenlandia species, while the mode of action of ursolic acid will spur further development of this valuable compound.
On the way moving forward, Associate Professor Marek Mutwil said, “Through our network of excellent collaborators, we were able to rapidly elucidate the biosynthetic pathway and mode of action of this poorly characterized medicinal plant. Our efforts now focus on developing new drugs based on ursolic acid by combining genomic and synthetic biology approaches.”
Dr Irene Julca added, “The genome represents a valuable resource to understand all the steps needed for the biosynthesis of active compounds enabling their industrial production and further development. Moreover, the methods used to identify the active compounds in O. corymbosa can be repurposed to study other plants.”
Read the paper here.