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

: 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 semisynthesis 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 (NABpaclitaxel, 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 nonribosomal 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.