Conjugation of Aspergillus flavipes Taxol with Porphyrin Increases the Anticancer Activity of Taxol and Ameliorates Its Cytotoxic Effects.

Ashraf S A El-Sayed,Basel Sitohy,Maher Fathalla,Shaima Morsy,Nabila Zein,Mahmoud Sitohy,Marwa A Yassin

doi:10.3390/molecules25020263

Ashraf S A El-Sayed, Basel Sitohy + Show 5 more

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https://doi.org/10.3390/molecules25020263

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Abstract

Taxol is one of the potential anticancer drugs; however, the yield of Taxol and its cytotoxicity are common challenges. Thus, manipulating the Taxol biosynthetic pathway from endophytic fungi, in addition to chemical modification with biocompatible polymers, is the challenge. Four fungal isolates, namely, Aspergillus flavipes, A. terreus, A. flavus, and A. parasiticus, were selected from our previous study as potential Taxol producers, and their potency for Taxol production was evaluated in response to fluconazole and silver nitrate. A higher Taxol yield was reported in the cultures of A. flavipes (185 µg/L) and A. terreus (66 µg/L). With addition of fluconazole, the yield of Taxol was increased 1.8 and 1.2-fold for A. flavipes and A. terreus, respectively, confirming the inhibition of sterol biosynthesis and redirecting the geranyl phosphate pool to terpenoids synthesis. A significant inhibition of ergosterol biosynthesis by A. flavipes with addition of fluconazole was observed, correlating with the increase on Taxol yield. To increase the Taxol solubility and to reduce its cytotoxicity, Taxol was modified via chemical conjugation with porphyrin, and the degree of conjugation was checked from the Thin layer chromatography and UV spectral analysis. The antiproliferative activity of native and modified Taxol conjugates was evaluated; upon porphyrin conjugation, the activity of Taxol towards HepG2 was increased 1.5-fold, while its cytotoxicity to VERO cells was reduced 3-fold.

Highlights

Taxol is a diterpenoid alkaloid firstly isolated from Taxus brevifolia [1,2] as a strong antimitotic agent, causing cellular arrest at the G2/M phase of tumor cells
The anticipation of fungi for commercial Taxol production has been challenged by their lower yield and drastic loss of Taxol yield with sub-culturing and storage [5,6,8,13,21]
After the 5th day of incubation, the fungal cultures were amended with fluconazole and AgNO3 (0, 2, 10, and 20 μg/mL final conc.), and incubation was continued for 20 days before Taxol was extracted and quantified

Summary

Introduction

Taxol is a diterpenoid alkaloid firstly isolated from Taxus brevifolia [1,2] as a strong antimitotic agent, causing cellular arrest at the G2/M phase of tumor cells. The anticancer activity of Taxol has been emphasized towards various tumor cell lines [3], including leukemia, breast, ovarian, and lung cancers [2,4], as well as against polycystic kidney diseases. Molecules 2020, 25, 263 extracted from the needles of T. baccata and T. walichiana growing in Europe and Asia. This method is challenged with lower yield, climatic dependence, and seasonal variations Chemical synthesis of Taxol has been emphasized [9,10]; the technical complexity and higher expenses are the main challenges stopping this technology from becoming an economically affordable approach [11,12]

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