Natural products and cancer: The urgent need to bridge the gap between preclinical and clinical research

Abstract

Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health, particularly when those reports contribute to both the understanding and therapeutics of cancer. For many decades, natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities. Recently, two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resveratrol and senegenin, two compounds widely present in herbal preparations used in traditional Chinese medicine. The first one, with comprehensive and recognized anticancer properties, and the second one, shows a compelling body of evidence supporting its neuroprotective effects, but with emerging anticancer activities. Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery. However, urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.

Core Tip: Natural products have been extensively investigated for their anticancer potential for many decades, and some are milestones in the history of anticancer drug discovery. However, despite the compelling data achieved by preclinical studies, the challenges to validate the clinical use remain ahead.

TO THE EDITOR

In this article we highlight the urgency of taking action in the design and execution of clinical trials of natural products, particularly plant-derived phytochemicals that have remained for decades in the preclinical studies phase. They continue to have the same status even though a substantial body of evidence has been gathered to demonstrate their anticancer actions.

An extensive body of evidence has unveiled the vast potential of naturally occurring compounds, particularly plant-derived phytochemicals, in managing many human diseases, including some types of cancers. Noteworthy, natural products are closely linked to the history of anticancer drug discovery, as were the cases of vinblastine, vincristine, and paclitaxel, just to mention a few[1-3]. The main purpose of this Editorial is to call attention to the urgent need to validate, through clinical trials, the vast preclinical data accumulated for decades in relation to the therapeutic potential of natural products in the treatment of cancer.

The urgency to keep going

Cancers are a leading cause of mortality, accounting for nearly 10 million annual deaths worldwide. Furthermore, cancer mortality has even surpassed cardiovascular disease-associated mortality in many high-income countries[4]. Notably, the estimated global economic cost of cancers from 2020 to 2050 is equivalent to an annual tax of 0.55% on global gross domestic product[5].

Several traditional Chinese medicine (TCM) prescriptions and active ingredients from herbal medicines have been used as part of the therapeutical approaches in many oncological diseases[6]. Resveratrol, a polyphenol commonly found in grapes and berries, is also present in many Chinese herbal medicines, such as Polygonum cuspidatum. Over the years, a huge body of preclinical studies has supported the anti-cancer activities of this polyphenol stilbene derivative. These activities are mainly focused on its ability to modulate many cellular signaling pathways involved in crucial biological events associated with tumor growth and development, such as oxidative stress, energy metabolisms, inflammation, apoptosis, autophagy, cell cycle control, angiogenesis, invasion, and metastasis[7-9]. The research conducted by Jiang et al[10] demonstrated that resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts. The data was raised by using several models including human pancreatic cancer tissue samples, pancreatic cancer cell lines, and in vivo tumor models.

Furthermore, convincing data demonstrate that resveratrol can also regulate the tumor microenvironment, a crucial contributor to tumor biology, by interfering with signaling pathways of some infiltrating cells as well as eliminating cancer stem cells, which are crucial elements in the development of resistance to therapy[11,12].

Senegenin, the active component of Polygala tenuifolia root is also widely used in TCM. For this triterpenoid sapogenin, the available data supporting its anti-cancer activities is rather scanty. Its main pharmacological activities are anti-oxidation, anti-inflammation, and anti-apoptosis, as well as those associated with neuroprotection, such as the clearing of the abnormal deposits of Aβ, inhibition of phosphorylation of tau, reduction of oxidative stress, and enhancing synaptic plasticity and learning and memory ability[13,14].

The study of Zhang et al[15] adds new evidence on the potential anti-cancer activity of senegenin, using various in vitro models of human hepatocellular carcinoma, which accounts for 80% of all human liver cancer cases. They demonstrated that this natural product has a profound effect on O-GlcNAcylation, a type of post-translational modification, which is crucial to connect altered nutrient availability to changes in cellular signaling and thus contributes to multiple aspects of tumor progression[16,17].

Despite thousands of preclinical studies on the anticancer activity of natural products, progress in translational research and clinical trials have been very limited. Thus, translating research breakthroughs into more effective cancer treatments remains a top priority for the scientific community. According to GLOBOCAN, new cancer cases show an alarming increase in incidence rate all over the world, expecting an increase of 47% from 2020 to 2040[18].

Clinical trials are essential for advancing new cancer treatments from the research lab to routine patient care. Although participation in clinical trials follows high-quality protocolsl[19], patient participation is notably low; fewer than 8% of individuals with cancer participate in these trials[20].

Patients may have serious fears and concerns that prevent them from enrolling in clinical trials, including the potential reduction of quality of life, the possibility of receiving a placebo treatment, the occurrence of unexpected side effects, and the belief that a drug in under development may not be the best therapeutic option for their diseases[21-23]. However, every clinical trial is conducted safely, undergoing review and approval by an independent panel of qualified physicians, researchers, and members of the Institutional Review Board. This oversight ensures the rights, safety, and welfare of all participants involved in any clinical trial.

In this regard, and far beyond the regulatory policies in every country, actions aimed at closing the gap between basic and clinical research are imperative. Additionally, scientific community-directed public education programs can help demystify all these fears and promote informed decisions about participating in clinical trials. This, in turn, may contribute to significant advancements in cancer treatments. Finally, international task forces could foster new initiatives for funding programs to support the natural products testing in cancer clinical trials.

CONCLUSION

The growing worldwide incidence of cancers and the extraordinary economic costs for both patients and health institutions, as well as the limitations of available conventional therapy, require many new efforts and resources to validate in clinical trials the potential of natural products in the treatment of cancer.