Cancer is the second leading cause of mortality after cardiovascular disease, with an estimated 9.6 million cancer related deaths in 2018 (GBD 2015). Cancer is a multifactorial disease characterized by the loss of growth factors that control the proliferation and division of cells. These abnormal malignant cells can evade the tumour suppressor factors of the human immune system, then develop to tumours and destroy adjacent tissues (Saeidnia and Abdollahi 2014). There are several treatments for cancer, administered according to developmental state of the disease. Chemotherapy, radiation therapy, surgery and immunotherapy are all important elements of cancer treatment. However, while many cytotoxic agents are known to Science (which could in principle serve as chemotherapeutic agents), only few of them specifically target tumour cells and are less toxic to regular, healthy human tissue (Petrelli et al. 2012; Cai et al. 2013; Zugazagoitia et al. 2016). Targeted therapy, usually the conjugated element for cancer treatments, delivers drugs to genes or proteins that are specific to cancer cells or the environmental tissues that promotes the growth of cancer (Padma 2015). Fungi are an importance source for natural product discovery, albeit most anticancer drugs are retrieved from plants and bacteria. In this entry, we describe several promising natural products derived from fungi and highlight some of the chief compounds that are currently in the clinical and preclinical developmental stage.
Irofulven (14) is a semi-synthetic derivative of illudin S (15), a natural toxin isolated from Omphalotus illudens (Jack O’Lantern mushroom; cf. Chin et al. 2006; Movassaghi et al. 2006). Irofulven interferes with DNA replication-complexes and cell division in DNA synthesis. The abnormal cells in S-phase lead to apoptotic cell death (Walser and Heinstein 1973; Jaspers et al. 2002). The antitumour activities of irofulven have been evaluated in phase I and II clinical trials with promising results against a variety of cancers, including those in the brain and central nervous system, breast, blood, colon, sarcoma, prostate, lungs, ovarian and pancreas (Alexandre et al. 2004; Miyamoto et al. 2018; Topka et al. 2018). Sandargo et al. (2019a) have recently described the state of the art, including some exciting new illudin conjugates that show superior in vitro activities than irufulven and are presently under early preclinical development.
Aphidicolin (16) is a tetracyclic diterpene with antiviral and antimitotic properties. The compound was originally isolated from “Cephalosporium aphidicola” (currently valid name: Akanthomyces muscarius) and later also reported from Nigrospora sphaerica (Bucknall et al. 1973; Starratta and Loschiavo 1974). Aphidicolin competes for the specific binding site on DNA polymerase α, δ, and ε enzymes. Its mechanism of action and efficacy have been intensively tested in clinical trials (Crosetto et al. 2013; Ayob et al. 2017), but so far it has not become a marketed drug.
Other anticancer lead compounds derived from fungi include leptosins F (17) and C (18) isolated from Leptoshaeria sp., which showed antitumor activity in mouse embryos (Yanagihara et al. 2005; Pejin et al. 2013); β-glucans, the polysaccharides that are naturally found on the cell walls of fungi (Chan et al. 2009; Bashir and Choi 2017); as well as palmarumycin (Powis et al. 2006) and spiropreussione A (Chen et al. 2009). The latter compounds, however, have only demonstrated these activities in vitro, and it is not clear whether they will eventually reach the late exploratory stage of preclinical development.