A recent Heliyon journal study discusses the role of fungal endophytes in the development of novel anti-cancer agents, particularly aimed at breast cancer therapy.
Study: Endophytic fungi: A future prospect for breast cancer therapeutics and drug development. Image Credit: Rattiya Thongdumhyu / Shutterstock.com
The role of endophytic bioactive metabolites in cancer treatment
In low- and middle-income countries (LMICs), the scarcity of resources and limited infrastructure significantly affect the provision of quick and effective cancer treatment, resulting in lower survival rates than advanced economies. In LMICs, targeted drugs such as cyclin-dependent kinase 4 (CDK4)/6 and anti-human epidermal growth factor receptor 2 (HER2) therapy are recurrently inaccessible.
Chemotherapy is a standard treatment option for cancer that is associated with several side effects. Short-term side effects of chemotherapy may include alopecia, muscle pain, fatigue, and neurocognitive dysfunction, whereas long-term effects may include infertility, psychosocial impacts, early menopause, secondary cancers, and cardiomyopathy.
Endophytic fungi have been synthesized for drugs such as vincristine, camptothecin, taxol, and podophyllotoxin. These fungi also produce unique secondary metabolites with novel structures.
The most frequently identified endophytic fungal species are Fusarium, Chaetomium, Pestalotiopsis, Penicillium, and Aspergillus. Some chemical groups that can be used to classify endophytic fungal metabolites are steroids, terpenoids, alkaloids, quinones, and others.
Torreyanic acid, from the endophytic fungus Pestalotiopsis microspore inhabiting Taxus taxifolia and Cytochalasins, are both endophytic fungi associated with anti-cancer properties. Camptothecin, obtained from endophytic fungi Entrophospora infrequens isolated from Nothapodytes foetida, is also a potent antineoplastic agent. Trametes hirsute and Podophyllum hexandrum produce podophyllotoxin and lignans, respectively, both of which have anti-cancer effects.
Endophytic fungi compounds used to treat breast cancer
Taxol is an anti-cancer drug belonging to the taxanes class of highly functionalized polycyclic diterpenoids. Moreover, taxol can be obtained from several genera of endophytic fungi, including Alternaria, Botryodiplodia Aspergillus, and Botrytis.
The antiviral and anti-cancer properties of Podophyllotoxin, an aryl tetralin lignan, have also been studied. Together with its analogs, Podophyllotoxin can effectively reduce the movement, invasion, and growth of breast cancer cells in both in vitro and in vivo models by interacting with topoisomerase II to prevent DNA replication.
Camptothecin is a highly effective anti-cancer agent originally discovered in the bark of Camptotheca acuminate. The endophytic fungus Entrophospora infrequent has also been identified as a potential source of camptothecin. Camptothecin interacts with topoisomerase I, which unwinds DNA supercoiling during the replication process.
Vinca alkaloids arise from the amalgamation of catharanthine monomer and vindoline. To date, vinca alkaloids have been shown to be clinically effective against both acute lymphoblastic leukemia (ALL) and nephroblastoma.
Toosendanin (TSN) has anti-cancer properties against several types of cancer. TSN suppresses the mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways, all of which are involved in cell arrest and apoptosis. TSN and isotoosendanin (ITSN) have also been shown to inhibit the growth of triple-negative breast cancer by inducing necrosis and autophagy.
Challenges and future perspectives
Natural compounds derived from endophytic fungi can overcome the significant toxicities associated with radiotherapy, chemotherapy, and surgery. Nevertheless, the artificial cultivation process of the compounds remains a challenge, as endophytic fungi may have unique nutritional requirements, require interaction with other microorganisms, or need specific signals to come out of dormancy that may be environment-driven and, as a result, absent in standard lab media.
To address these challenges, current isolation methods should be refined, and novel bioengineering systems should be developed. Metabolomic analysis could be used to mimic the natural habitats of endophytic fungi and identify specific nutrient formulations. Co-culturing systems could also aid in microorganism interaction.
Genetic engineering may allow researchers to modify fungi and improve the reliance on specific signals or nutrition. Furthermore, omics technologies could be used to inform media formulation and identify key proteins for adaptation to artificial growth conditions.
Other challenges impeding progress in this field include low yield, limited understanding of the complex biochemical interactions, and difficulties expanding production. Ongoing efforts to mitigate these challenges include using automation, enhancing bioreactor designs, and customizing fungal strains to maximize yield. Collaboration between the government, industry, and academia may also advance efforts to develop endophytic metabolites into viable therapeutic molecules.
Regional and international repositories should be created to store endophytic cultures, preserving cultures from threatened species or plants and extending their availability to the wider scientific community for further research. A database on bioactive compounds should also be maintained, as this tool could support the identification of novel compounds and elucidate their mechanism of action.
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