Taxol (Paclitaxel): A Novel Alkaloid with Anticancer Potential

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Respected Editor-in-Chief,

Paclitaxel (C₄₇H₅₁NO₁₄) is a therapeutic agent used in cancer treatment, belonging to the taxane class, which is part of the diterpene family. Originally extracted from the bark of the Pacific yew tree (Taxus brevifolia), a member of the Taxaceae family, it received FDA (Food and Drug Administration) approval in 1993 and has been listed among the World Health Organization's (WHO) Essential Medicines since then. Marketed under the brand name Taxol, it has demonstrated effectiveness against a wide range of cancers, including those of the lung, breast, ovary, bladder, prostate, melanoma, cervix, esophagus, pancreas, and colorectal areas, as well as Kaposi sarcoma [1, 2].

Taxol, like other drugs in the taxane category, interferes with microtubule functions. Microtubules are essential intracellular structures involved in various critical processes in eukaryotic cells, such as cell movement, nuclear and cellular division, and the maintenance of cellular architecture. Taxanes stabilize tubulin bound to GDP, thereby preventing its depolymerization and disrupting mitotic spindle formation, chromosome separation, and cell division. Like other anticancer alkaloids such as vincristine, vinblastine, and vinorelbine from the Vinca genus and colchicine from Colchicum, paclitaxel acts as a mitotic inhibitor. Although these substances have distinct effects on microtubule dynamics, they are all directed towards microtubules. Additionally, paclitaxel promotes apoptosis by inhibiting the apoptosis regulator protein Bcl-2 (B-cell leukemia 2) [3]. Paclitaxel induces apoptosis by blocking the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2) [4].

Usually given intravenously, paclitaxel can be prepared with albumin, alcohol, and/or emulsifier. Its cytotoxic effects depend on time as well as concentration.

In an in vitro study, ascorbic acid improved the antineoplastic potential of paclitaxel in human breast carcinoma cells. Caffeic acid phenethyl ester (CAPE) has selective estrogen receptor modulators (SERM) activity, and it increases the proapoptotic effects effect of paclitaxel on prostate cancer cells (PC-3, DU-145, and LNCaP) prostate cancer cells [5]. A cell-penetrating peptide (CPP)-taxol conjugate (Taxol–CPP) was synthesized, self-assembled nanospheres, and showed cytotoxicity against HepG2 cancer cells. Nanoxel, a nanoparticle formulation of the taxol has been approved by the Indian regulatory authority [4]. Mice bearing NSCLC (non-small cell lung cancer) xenografts, when administered with nanoparticles loaded with paclitaxel and cisplatin showed better control of tumor growth [6].

However, drug resistance is a deterrent in the prolonged usage of Taxol. The upregulated expression of TXNDC17 is associated with resistance in colorectal cancer cells. The high levels of phospho-STAT3 and TXNDC17 production are induced by taxol [6]. A study found that taxol-resistant cells expressed higher levels of TAK1 (transforming growth factor-β-activated kinase 1). Taxol-resistant human ovarian cancer specimens were more susceptible to taxol-oligoarginine conjugates [6]. Apart from drug resistance, taxol shows side effects, which can lead to patient non-adherence. Some of the adverse effects include hives, wheezing, poor hair quality, alopecia, muscle pains, arthralgia, tingling sensation, dizziness, peripheral neuropathy, diarrhea, female infertility, bone marrow suppression, etc. In some patients, vascular issues can occur. The fetus may become teratogenic as a result of the administration to pregnant mothers. Due to its limited water solubility, taxol is frequently combined with the formulation vehicle cremophor, which might lead to unfavorable effects. Thus, ongoing pharmacovigilance regarding taxol, drug-herb interactions, and drug-drug interactions must be practiced [6]. Apart from the plant, taxol has been isolated from the endophytic fungus Paraconiothyrium variabile and Epicoccum nigrum. Other fungi such as Metarhizium anisopliae, Pestalotiopsis microspora NK17, and Cladosporium species also elaborated taxol in culture medium. Cladosporium cladosporioides MD2 produce taxol at levels up to 800 μg/L. Aspergillus aculeatinus Tax-6 also produced taxol in culture conditions. The taxol biosynthetic gene has been identified to be dbat, pgα1, etc. Apart from different Taxus species, paclitaxel has been detected in hazel plants from the Betulaceae family. In plants, paclitaxel is synthesized by the terpenoid pathway. Semisynthetic taxol is generated using plant metabolite baccatin III; plant cell culture techniques; and metabolic engineering of bacteria. Apart from the anticancer usage, paclitaxel is being used for other therapeutic purposes. Paclitaxel eluting stents are used for vascular diseases [6]. Hence, other taxol possibilities and scopes to circumvent its adverse effects ought to be explored. Figure 1 illustrates the biological mechanism of taxol.