Docetaxel: activity, mechanism of action and pharmacokinetics

General Description

Chemotherapy drug Docetaxel has been found to have potent anti-cancer activity and is effective against various tumors, including breast cancer and colon cancer. Recent research has also revealed its promising effects in promoting the biogenesis of high-density lipoprotein (HDL), which plays a crucial role in preventing heart disease and atherosclerosis. It inhibits the cell-surface protein DSC1, which negatively regulates HDL biogenesis and increases the level of circulating HDL in the bloodstream. Additionally, Docetaxel has been shown to inhibit the proliferation of vascular smooth muscle cells which contribute to the development of atherosclerosis, reducing dyslipidemia-induced atherosclerosis in animal models. It achieves this through targeted inhibition of PFKP-mediated glycolysis. Docetaxel targets the Smad3/HIF-1α signaling pathway to inhibit tumor Warburg and proliferation in prostate cancer cells. Preclinical pharmacokinetics studies in mice showed that docetaxel primarily undergoes hepatic and biliary elimination, with minimal urinary or pulmonary excretion. These findings highlight the potential for Docetaxel and other HDL-directed therapies to prevent and treat atherosclerosis while providing a promising treatment option for various cancers.

Figure 1. Docetaxel injections

Activity

Anti-cancer activity

Docetaxel demonstrates potent in vivo antitumor activity against various murine transplantable tumors, including melanoma, pancreatic ductal adenocarcinoma, and colon adenocarcinoma, as well as breast tumors in subsequent studies. It exhibits higher efficacy than paclitaxel in most cases, with schedule-independent activity and potential for synergism with other cytotoxic drugs. Docetaxel has demonstrated significant inhibitory activity in numerous human and murine cell lines, particularly against leukemia, epidermoid carcinoma, small-cell lung carcinoma, bladder carcinoma, ovarian cancer, endometrial cancer, colon cancer, and breast cancer cell lines. Its superiority over paclitaxel is attributed to its stronger binding to microtubules and lower efflux and dissociation from microtubules. ¹

Promote High-Density Lipoprotein Biogenesis

Docetaxel is a chemotherapy drug that has been found to have promising effects in promoting high-density lipoprotein (HDL) biogenesis. Recent research has identified the cell-surface protein DSC1 as a negative regulator of HDL biogenesis. DSC1 sequesters apolipoprotein A-I, which is a key component of HDL, and prevents its assembly into mature HDL particles. By inhibiting this process, docetaxel promotes HDL biogenesis and increases the level of circulating HDL in the bloodstream. Furthermore, studies have shown that docetaxel has other beneficial effects on vascular health. It can inhibit the atherogenic proliferation of vascular smooth muscle cells, which are the cells that contribute to the development of atherosclerosis by forming plaques inside arterial walls. Docetaxel has also been shown to reduce dyslipidemia-induced atherosclerosis in animal models. The discovery of DSC1 as a druggable target for the promotion of HDL biogenesis has opened up new opportunities for the development of therapies to prevent and treat atherosclerosis. ²

Mechanism of action

Docetaxel inhibits cell proliferation in prostate cancer cells by targeting PFKP-mediated glycolysis. It reduces Smad3 nuclear translocation through the decreased phosphorylation of Ser213 and inhibits the binding of Smad3 to the promoter of the HIF-1α gene, suppressing transcriptional activation of HIF-1α. Docetaxel-treated cells also exhibit disrupted endogenous regulation and interaction between Smad3 and HIF-1α. The expression of both HIF-1α and PFKP is significantly reduced in prostate cancer receiving docetaxel treatment in vivo. These findings indicate that docetaxel targets the Smad3/HIF-1α signaling pathway to inhibit tumor Warburg and proliferation in prostate cancer cells. ³

Pharmacokinetics

Through HPLC analysis, preclinical pharmacokinetics of docetaxel in mice showed biexponential decline of plasma concentration following bolus doses, with a linear relationship between dose and AUC. Tumor concentrations were higher than the ICs0 of tumor cell lines studied. Elimination was primarily hepatic and biliary, with minimal urinary and pulmonary excretion, yielding three major metabolites. Radioactivity was detected in all tissues except for the CNS, and several unidentified metabolites were recovered in urine, each representing less than 2% of the administered dose. No sex-associated pharmacokinetic differences were observed. ⁴

Reference

1. Cortes JE, Pazdur R. Docetaxel.J Clin Oncol, 1995, 13(10):2643-2655.

2. Choi HY, Iatan I, Ruel I, et al. Docetaxel as a Model Compound to Promote HDL (High-Density Lipoprotein) Biogenesis and Reduce Atherosclerosis. Arterioscler Thromb Vasc Biol, 2023, 43(5):609-617.

3. Peng J, He Z, Yuan Y, et al. Docetaxel suppressed cell proliferation through Smad3/HIF-1α-mediated glycolysis in prostate cancer cells. Cell Commun Signal, 2022, 20(1):194.

4. Bissery MC, Renard A, Montay G, et al: Taxotere: Antitumor activity and pharmacokinetics in mice. Proc Am Assoc Cancer Res, 1991, 32:401.

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