Sub-acute Toxicity Assessment of Taxol Isolated From Fusarium Solani, an Endophytic Fungus of Taxus Brevifolia, in Wistar Rats and Analyzing Its Cytotoxicity and Apoptotic Potential in Lung Cancer Cells

Abstract

The limited availability of taxol from plant sources has prompted the scientific world to look for an alternative, as in the chemical synthesis of tissue cultures of the Taxus species, to meet the increasing demand for the drug. However, these alternative means are expensive or result in low yield. Previously, we have reported that Fusarium solani isolated from Taxus celebica produced taxol and its precursor baccatin III in liquid-grown cultures, and it exhibited promising anticancerous effects in certain cancer cell lines. In the present study, we examined the sub-acute toxicity of fungal taxol (FS) in Wistar rats according to the Organization for Economic Cooperation and Development (OECD) guidelines. The sub-acute oral administration of FS up to 500 mg/kg for a period of 28 days appears to be safe in rats and did not cause severe treatment-related toxicity or treatment-related death. The observed changes in body weight, histopathology, hematological and biochemical parameters, and organ weight were not significant compared to those in the control group of animals. The results suggest that FS is relatively safe when administered orally in rats. The antiproliferative and apoptosis-inducing activities were studied in A549 (human lung cancer) cell line. FS arrested the cells at S and G2/M phases, leading to apoptosis. The characteristic molecular signatures of apoptosis, such as externalized phosphatidyl serine, DNA fragmentation, and nuclear and chromatin condensation, were observed upon FS treatment. FS triggered the generation of reactive oxygen species in A549 cells and elicited cell death by both extrinsic as well as the mitochondria-mediated intrinsic pathway of apoptosis. These results indicate that endophytic fungi isolated from medicinal plants may serve as potential sources of anticancerous compounds with little side effects.

Isolation and characterization of N‐(2‐Hydroxyethyl)hexadecanamide from Colletotrichum gloeosporioides with apoptosis‐inducing potential in breast cancer cells

“…63 Apoptotic morphology indicated by nuclear shrinkage and chromatin condensation in cancer cells has been visualized through DAPI assay upon treatment with different concentrations of Taxol purified from Fusarium solani. 64 Cell-shrinkage and morphological changes indicating cell damage has been shown in a report through DAPI assay upon treatment of cells with taxol isolated from endophytic fungi, Cladosporium oxysporum. 65 Studies on morphological and time-lapse analyses reveal that the collective movement of cancer cells is crucial for several processes, such as invasion and metastasis.…”

The endophyticFusariumstrains: a treasure trove of natural products

“…It inhibited cell proliferation of a number of cancer cell lines such as HeLa, HepG2, Jurkat, Ovcar3 and T47D with IC 50 values ranging from 0.005 to 0.2 μM for fungal taxol. 20 It induced apoptosis in JR4-Jurkat cells with a possible involvement of anti-apoptotic Bcl 2 and loss in mitochondrial membrane potential and was unaffected by inhibitors of caspase-9, -2 or -3 but was prevented in the presence of caspase-10 inhibitor. 20 However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens.…”

“…20 It induced apoptosis in JR4-Jurkat cells with a possible involvement of anti-apoptotic Bcl 2 and loss in mitochondrial membrane potential and was unaffected by inhibitors of caspase-9, -2 or -3 but was prevented in the presence of caspase-10 inhibitor. 20 However, signicant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. 21 F. solani was the only one strain among 153 endophytic fungi recovered from the roots, stems, and leaves of Cajanus cajan that was found to produce vitexin (5,7,4-trihydroxyavone-8-glucoside) (25), which is well known to have valuable biological properties such as anti-inammatory, anticancer, anti-nociceptive, antioxidant, anti-convulsant, cardioprotective, hypotensive, memory enhancing potential, and anti-diabetic.…”

Cedrus atlantica extract exerts antiproliferative effect on colorectal cancer through the induction of cell cycle arrest and apoptosis

“…For centuries, extensive research has been conducted on drug discovery and development from plant extracts and natural products, which contain numerous molecules with proven cytotoxicity inducing apoptosis via different signaling pathways against cancers (Benarba & Pandiella, 2018 ). For example, anticancer compounds such as Vinca alkaloids isolated from Catharanthus roseus (Shams et al., 2009 ), podophyllotoxin isolated from Podophyllum peltatum (Ardalani et al., 2017 ), camptothecin isolated from Camptotheca acuminata (Ran et al., 2017 ), taxol isolated from Taxus brevifolia (Kuriakose et al., 2020 ), and their derivatives are widely used as first‐line and second‐line cancer therapies.…”