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.

Gini C Kuriakose,Ramachandra Subbaraya Gudde,B P Arathi,M V Jiby,C Jayabhaskaran,Mangalath Divya Lakshmanan

doi:10.3389/fonc.2020.538865

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 Co-operation 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.

Highlights

Taxol is a diterpenoid isolated initially from the stem or bark of the Pacific yew tree (Taxus brevifolia)
Taxol, purified from F. solani, isolated from the stem cutting of T. brevifolia [25] previously from our laboratory was used in the study
Taxol was identified based on highperformance liquid chromatography (HPLC) by comparing the retention time to the standard peaks [25]

Summary

INTRODUCTION

Taxol is a diterpenoid isolated initially from the stem or bark of the Pacific yew tree (Taxus brevifolia). We have demonstrated the effect of taxol from Fusarium solani, an endophytic fungus of Taxus brevifolia, on cancer cell inhibition and apoptosis induction in various human carcinoma cell lines [13]. Taxol attains its antitumor activity by promoting tubulin dimerization and inhibiting the depolymerization of microtubules, resulting in the formation of abnormally stable and non-functional microtubules [14, 15] With this action, exposure to taxol prevents the completion of mitosis, resulting in mitotic metaphase arrest and cellular toxicity [16]. We have evaluated the sub-acute toxic effects of fungal taxol administered through oral route with Tween 80 at 2% as vehicle in an animal model and elucidated the molecular mechanism of FSinduced apoptosis in non-small cell lung cancer (NSCLC) cell line A549

MATERIALS AND METHODS

RESULTS AND DISCUSSION

ETHICS STATEMENT