Rescuing and utilizing anticancer Nothapodytes species: Integrated studies from plant resources to natural medicines

Abstract

Cancer remains the second leading cause of death globally, following cardiovascular disease, and represents a major public health challenge.¹ It arises from extensive DNA damage induced by ultraviolet radiation, ionizing radiation, environmental factors, and therapeutic agents. Among cancer types, the most frequently diagnosed are lung (12.7%), breast (10.9%), colorectal (9.7%) and gastric cancers (7.8%).² In China, lung cancer accounts for the highest cancer mortality, with 657 000 deaths (27.2%) and a crude mortality rate of 47.5 per 100 000 individuals.³ According to the World Health Organisation, cancer contributes to the largest global disease burden, with 244.6 million disability-adjusted life years (DALYs) lost, affecting both men (137.4 million DALYs) and women (107.1 million DALYs).⁴ Consequently, there is an urgent need for more effective medications and therapeutic strategies to reduce mortality, minimize side effects, and improve patient prognosis.

While conventional anticancer treatments, such as surgery, radiotherapy and hormonal therapy, have advanced, the field of cancer therapeutics is intensively focused on improving survival outcomes.⁵ Emerging therapies, including immunotherapy, gene therapy, and molecular-targeted treatments, show particular promise in enhancing efficacy.⁵ Among these, molecular-targeted therapy has gained attention for its ability to directly interfere with oncogenic molecules, effectively blocking sites critical to cancer progression.⁶ Over the past decade, antibody-drug conjugates (ADCs), which combine a monoclonal antibody with a cytotoxic drug linked by a chemical bridge, have achieved substantial success, due to their highly selective delivery of toxic agents to cancer cells.⁷ Consequently, exploring diverse therapeutic strategies remains essential for advancing anticancer drug development.

Small-molecule drugs play a critical role in chemotherapy for treating malignant and metastatic diseases. Over 60% of current anticancer drugs originate from natural sources, including plants, animals and microbes.⁸ For instance, vinblastine and vincristine from Catharanthus roseus (Apocynaceae), taxol and docetaxel from Taxus species (Taxaceae) and camptothecin (CPT) from Camptotheca acuminata (Nyssaceae) are among the most effective cancer chemotherapeutics available today.⁹ However, the primary challenge in developing nature-derived anticancer drugs is the limited availability of natural resources. Taxol, known for its high efficacy, low toxicity and broad-spectrum activity, is a textbook case of this challenge. To meet demand, large quantities of Taxus trees have been felled. This substantially contributed to the depletion of these resources, which is critical since these trees have a long developmental cycle. Currently, all 11 Taxus species are listed on the International Union for Conservation of Nature Red List of Endangered Species as of 2013.

Camptothecin is a monoterpene indole alkaloid that specifically targets DNA topoisomerase I and is recognized as the third most significant anticancer drug after taxol and vinblastine.¹⁰ With a total trade volume exceeding $10 billion, CPT continues to be a focus for the development of potent and safer anticancer drugs. Modifications to CPT's structure have produced several derivatives, such as irinotecan, topotecan, and belotecan, with enhanced antitumor activity and improved stability, achieved by introducing hydrophilic amino and hydroxyl groups to the A/B rings of CPT.¹¹ Additionally, CPT is increasingly utilized as a payload in ADCs and small-molecule drug conjugates, optimizing its therapeutic potential.¹²

Because Nothapodytes species contain 3–7 times more CPT than Camptotheca acuminata, the genus Nothapodytes has become the primary source of CPT since 2003. However, the nine Nothapodytes species, primarily distributed across tropical regions of southern and southeastern Asia, have been overexploited. In particular, over 80% of Nothapodytes plants in Southwest China have been depleted, with only a small number of plants now surviving in protected natural areas (unpublished data). Thus, we urgently call for the conservation, protection and sustainable use of all Nothapodytes species to preserve these valuable anticancer resources.¹

In conclusion, conserving threatened medicinal plant species with broad distribution requires a multifaceted approach. We should prioritize studies on plant resources within target taxa, encompassing biogeography, systematics, and distribution. Equally important is understanding the diversity and accumulation mechanisms of active compounds across spatial and temporal scales, alongside photosynthetic and physiological influences on target compound production. Additionally, assessing the ecological role of active compounds under biotic or abiotic pressures, including symbiotic interactions with endophytic bacteria or fungi that may contribute to compound synthesis, is essential. Investigating the biosynthesis pathways of these compounds, as well as their pharmacokinetics and pharmacodynamics, will further support conservation efforts.

Moreover, policy standards must be established to protect these target species, alongside evaluating their conservation status and enhancing sustainable plant resource supply. Strengthening the pharmaceutical development pipeline, from plant resources to active ingredients, lead compounds, and natural medicines, will be crucial for integrating conservation with advances in pharmacology (Figure 1).

Conceptulization: Gao Chen, Xianghai Cai, Jia Tang, Jia Ge. Formal analysis and investigation: Gao Chen, Xingrong Peng. Writing—original draft preparation: Xingrong Peng. Supervision: Gao Chen.

The authors declare no conflict of interest.