Looking at the potential of South African medicinal plant extracts for cancer therapies - Fellows' seminar by Tshepiso Makhafola

“Our overarching goal is investigating the therapeutic potential of plants in South Africa and developing novel approaches to new mechanisms of action,” said Tshepiso Makhafola of the Department of Health Sciences at the Central University of Technology. Makhafola is in the eighth cohort of Iso Lomso fellows and is in his first residence. Inspired by memories of community using plants to heal various conditions, Makhafola is determined to understand how compounds derived from South African plants and the extensive indigenous knowledge behind them could be used to tackle some of the most devastating diseases of our time – like cancer. “The global incidence of cancer is increasing over time, and it’s estimated that one in nine individuals will develop cancer in their lifetime. Cancer is the second-leading cause of global mortality,” he said. “In 2020 there were 20 million new cases and 10 million deaths globally. By 2050 it’s estimated that there will be 35.5 million new cases and 18.5 million deaths. This is the impetus driving us to find new treatments and preventive therapies.” Makhafola also pointed out that 254 new drugs were approved by the US Food and Drug Administration between 2015 and 2020 but only 29% (71) were for cancers. Even for those drugs that make it through the stringent clinical trials and registration processes, “the costs, side effects and potential to develop resistance all bring problems,” he continued. “In addition, price and access remain problematic in the Global South. We urgently need complementary and alternative medicines.” Throughout history, plants have been an important source for medicinal use − codeine, digitoxin and quinine all come from plants. “Traditional medicine has a long history and is still the major source of medicine in developing countries. Approximately 70% of the South African population consult traditional healers for their primary healthcare, perpetuating the need for scientific appraisal of traditional medicine to establish its efficiency and safety,” said Makhafola. “Additionally, pharmacological and phytochemical insights into several plants have led to the discovery of novel chemicals and therefore novel drugs. It’s estimated that more than 60% of anti-cancer drugs in clinical use originate from or are inspired by natural products, pointing to their importance as promising sources for cancer drug development.” “Plants specifically are a valuable source of pharmacologically important proteins,” he added.

Different approaches

Makhafola pointed out that his group of young, enthusiastic researchers is looking at several approaches. His STIAS project specifically investigates the anti-cancer splicing effects of selected South African medicinal plants to elucidate their mechanisms of action and identify possible druggable biomarkers/targets. In addition, their in vivo anti-tumour effects will be investigated in preclinical and clinical trials using tumour grafts and patient-derived xenografts. He explained that oncogenesis – the process by which normal cells turn into cancer cells − is associated with gene-splicing switches. Gene splicing allows a single gene to produce multiple different proteins generating multiple mRNAs. Splicing plays a major role in cancer determining tumour progression and also the development of resistance to therapies. Alternative splicing can disrupt regular splicing and hopefully slow down cancer formation. “My project is therefore looking at how we can develop suppressor not promoter proteins,” said Makhafola. “Analysis of modulating cancer-specific alternative splicing is a promising step forward in basic and translational molecular biology.” Makhafola’s current focus is anti-cancer therapies against colorectal and oesophageal cancer. Colorectal cancer and oesophageal cancer are ranked the third and eighth most common cancers worldwide and have a global mortality rate of 5.8 and 5.3%, respectively. In South Africa, colorectal is the fourth most common cancer, with a low survival rate of 8.1%. Thus far Makhofola’s group have investigated the effect of an extract of a South African medicinal plant, Cotyledon orbiculata, on the survival of colon oesophageal cancer cell lines showing that it is able to induce apoptosis (death) in these cell lines through alteration in splicing of specific RNA binding transcripts. They have also found that compounds isolated from Sarcocephalus pobeguinii have good in vitro anti-proliferative and anti-inflammatory effects and that extracts from African Mistletoes (Loranthaceae) can exert anti-inflammatory and acetylcholinesterase inhibitory potentials. In addition, they have found possible anti-breast cancer mechanisms of novel substituted salicylidene-based compounds in regulating key molecular targets of breast-cancer development. “We are interested in investigating all pathways as possible targets,” he said. In addition to cancers, the group are also working on possible plant therapies for diabetes and discovery of antimicrobial compounds active against multi-drug resistant microorganisms. .

A challenging space 

But Makhafola emphasised the huge challenges facing young researchers in this area including the need to ensure that promising research can be translated into products that can be used. This involves understanding and being able to work through all the value-chain processes from preclinical to clinical studies, patenting and regulatory processes.  It also often means competition with countries in the Global North. “The sad reality is that we just do research. Our survival as academics depends on publishing first so we can’t always investigate other possibilities. Young academics are dependent on publication outputs for promotion. Although it is changing, patenting is still of no value to their immediate career. There is a need to disrupt the rules and the system.” “If Big Pharma and other stakeholders wanted to work with us, we would have no problem,” he added. “The problem is they want to buy you out. It’s also complicated negotiations. We need proper spin-out companies to focus on getting things into production.” He also questioned the regulatory processes on single-molecule therapeutics/entities. “I don’t think a single therapy is the way to go – this doesn’t make sense in Africa where extracts containing multiple compounds are mostly used. If we want inexpensive treatments, we need to standardise the preparations already used in communities.” And this also means ensuring that the original owners of the knowledge are not exploited. “It’s been proven over time that traditional healers and communities have been exploited. We must involve them in the value chain and ensure that the owners of the indigenous knowledge benefit.” “We are trying to advocate for the standardisation of traditional and complementary medicines if their safety can be guaranteed.” Michelle Galloway: Part-time media officer at STIAS Photograph: SCPS Photography