Drugs That Changed Society: Microtubule-Targeting Agents Belonging to Taxanoids, Macrolides and Non-Ribosomal Peptides

Abstract

During a screening performed by the National Cancer Institute in the 1960s, the terpenoid paclitaxel was discovered. Paclitaxel expanded the treatment options for breast, lung, prostate and ovarian cancer. Paclitaxel is only present in minute amounts in the bark of Taxia brevifolia. A sustainable supply was ensured with a culture developed from Taxus chinensis, or with semi-synthesis from other taxanes. Paclitaxel is marketed under the name Taxol. An intermediate from the semi-synthesis docetaxel is also used as a drug and marketed as Taxotere. O-Methylated docetaxel is used for treatment of some paclitaxel-resistant cancer forms as cabazitaxel. The solubility problems of paclitaxel have been overcome by formulation of a nanoparticle albumin-bound paclitaxel (NAB-paclitaxel, Abraxane). The mechanism of action is affinity towards microtubules, which prevents proliferation and consequently the drug would be expected primarily to be active towards cancer cells proliferating faster than benign cells. The activity against slowly growing tumors such as solid tumors suggests that other effects such as oncogenic signaling or cellular trafficking are involved. In addition to terpenoids, recently discovered microtubule-targeting polyketide macrolides and non-ribosomal peptides have been discovered and marketed as drugs. The revolutionary improvements for treatment of cancer diseases targeting microtubules have led to an intensive search for other compounds with the same target. Several polyketide macrolides, terpenoids and non-ribosomal peptides have been investigated and a few marketed.

Nab-Paclitaxel for Relapsed AIDS-Related Kaposi Sarcoma -A Case Report

“…Nab-paclitaxel is used in the treatment of advanced pancreatic cancer, breast cancer, and non-small cell lung cancer. 11 …”

Ultrasonic Film Rehydration Synthesis of Mixed Polylactide Micelles for Enzyme-Resistant Drug Delivery Nanovehicles

“…Paclitaxel is one of the key drugs in anticancer therapy [ 78 ]. Despite a long history of application, there are still problems of side toxicity, low solubility, multidrug resistance and fast clearance of this drug in the human body.…”

“…So, the search for effective drug delivery forms for PTX is still challenging. The intravenous route of administration of PTX is the major method for treatment [ 72 , 73 , 78 , 79 ]. For this purpose, different carriers of amphiphilic and polymeric structures are developing [ 9 , 11 , 15 , 18 , 46 , 61 , 72 , 78 ].…”

Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma

“…Five distinct sites on the β-tubulin subunit have been targeted by MTAs, and an additional binding site has been identified on α-tubulin. MTAs can be categorized into those that inhibit polymerization (tubulin destabilizers, e.g., vinca alkaloids and colchicine) and those that inhibit depolymerization (tubulin stabilizers, e.g., taxanes and epothilones) [3]. In the clinic, they are utilized as both a first-and second-line standard of care in a variety of solid and hematological malignancies that lack targeted therapies.…”