A recently published study from our Natural Product Drug Discovery Group (NPDD) highlights a novel screening method in uncovering the next generation of antimitotic natural compounds. The study, entitled ‘Purification, identification, and characterization of two benzophenanthridine alkaloids from Corydalis longicalcarata rhizomes with anti-mitotic and polyploidy-inducing activities’, was published in “Phytochemistry Letters”, an Official Journal of the Phytochemical Society of Europe, on 7th January 2021. The research, led by the first author Jinhua Li and supervised by Dr. Jing Zhang, Co-director of MBICR, represents a cross-disciplinary teamwork between the MBICR Discovery Oncology (DO) group and NPDD group and also a collaboration with Anticancer Bioscience, Ltd. 

This study uncovers a previously unknown antimitotic activity for the phytochemicals corynoline and acetylcorynoline, discovers their potential to be developed as anticancer drugs, and highlights their pleiotropic effects on cell division, including prevention of chromosome congression, compromise of spindle checkpoint response, and blockage of cytokinesis.

To choose an invaluable mitotic target for cancer therapy, Dr. Zhang turned to a finding by Dr. Dun Yang and his Nobel laureate mentor Dr. J. Michael Bishop, which uncovered a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein by disabling the chromosomal passenger protein (CPP) complex. Collaborating with Dr. Dun Yang and being equipped with a prior understanding of the versatile functions of the CPP complex in orchestrating karyokinesis and cytokinesis, Dr. Zhang’s research group designed its assay to score for phenotypes typically seen when the CPP complex is disabled. 

Specifically, the parameters for a positive hit are a temporary elevation of mitotic index (MI) at 24 hours of drug treatment and an accumulation of polyploid cells at 48 hours of drug treatment, indicative of mitotic arrest and cytokinetic failure respectively. With the knowledge that both phenotypes ensue from the inhibition of the CPP complex, the researchers could exclude compounds that elicited only a prolonged arrest of cells in mitosis, a phenotype typically provoked by spindle toxins. “In theory, this mechanism-informed, high-throughput screening assay is suitable to identify any compound that disables the CPP complex or a component either upstream or downstream of the complex in the cell division process,” says Dr. Jing Zhang.

This research conducted a phenotypic screen for the specific anti-mitotic activity using an in-house natural products library composed of 17,000 crude extracts from more than 2,000 different plant species (Figure 1).

An ethanol extract from the rhizomes of Corydalis longicalcarata (Papaveraceae) was identified with the desired activity. In the bioassay-guided isolation and purification of this anti-mitotic activity that followed, the bioactive molecules were identified as corynoline and acetylcorynoline (Figure 2). These molecules are known to have pharmacological activities such as acetylcholinesterase inhibitory activity, inhibition of cell adhesion, or inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) 7, to name a few, but their anti-mitotic effects were not identified previously.

Jinhua Li, the first author of the research article, finds that our research discovered a previously unknown antimitotic activity for these known phytochemicals- corynoline and acetylcorynoline. These two bioactive molecules have distinct anti-mitotic effects more effective than the spindle toxins. For instance, these phytochemicals can elevate the mitotic index, transiently arrest cells in prometaphase, compromise the spindle checkpoint response, and ultimately induce polyploidy by preventing cytokinesis. Although both compounds mimic the disablement of the CPP complex, they fail to inhibit Aurora B kinase, the catalytic subunit of the CPP complex. The target disabled by these two phytochemicals is still a mystery. Nevertheless, corynoline and acetylcorynoline can serve as prototypic molecules and have significant potential to be developed as specific anticancer therapeutics.

“The study offered eye-opening insights on the requirement and ability of novel bioassays to unlock new functions for known phytochemicals. These compounds may serve as scaffolds for modifications to develop more potent antimitotic therapeutics with less severe side-effects. We are confident that further exploration in this direction will enable us to develop breakthrough precision cancer therapies that are safer and more effective,” says Dr. Dun Yang, Director of MBICR. 

Natural products and their derivatives still remain the best source of drugs and drug leads, as much as they have been invaluable historically in small-molecule therapeutics. Data shows that synthetic libraries fail to deliver their promises and that natural products are more effective as sources for drugs despite challenges such as the lack of compatibility of natural-product extract libraries with high-throughput screening. “J. Michael Bishop Institute of Cancer Research is committed to constructing the most extensive natural products library in the world and, when completed, it will provide world-wide scientists an unprecedented chemical diversity to screen for drug leads and interrogate biological processes,” says Dr. Jing Zhang.

For more information about this study, see https://doi.org/10.1016/j.phytol.2020.12.001.

Anticancer Bioscience (ACB) is an international private company, commercializing discoveries emerging from China’s world-leading cancer research at the J. Michael Bishop Institute of Cancer Research. Pioneers in synthetic lethal approaches to precision oncology and experts in MYC biology and cell division, ACB was founded in 2016 in Chengdu, China. 

The J. Michael Bishop Institute of Cancer Research (MBICR) is a nonprofit organization that focuses on research projects with excellent potential for both basic sciences as well as translational science applications.  Named after the Nobel laureate Dr. J. Michael Bishop and advised by a group of world-class scientists, the Institute was founded in 2017 in Chengdu, China.

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SOURCE Anticancer Biosciences