Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive toS-Trityl-l-Cysteine–Mediated Eg5 Inhibition

Abstract

Castrate-resistant prostate cancer remains a major clinical challenge. Due to the toxicity profile of taxane-based chemotherapy and treatment failure in some patients, novel agents with improved efficacy to side effect profiles are urgently needed. Eg5, a member of the kinesin-5 family, controls the formation of the bipolar spindle during cell division, and suppressed Eg5 function leads to mitotic arrest. S-Trityl-Lcysteine (STLC) is a novel Eg5-specific small-molecule inhibitor. Here, we report the first study to evaluate its use in prostate cancer. In a panel of prostate cancer cells, LNCaP and PC3 cells were the most and least sensitive to STLC treatment, with a 7.2-fold difference in their respective GI 50 values: 250 nmol/L and 1.8 μmol/L. In LNCaP cells, treatment with either STLC or docetaxel resulted in transient G 2 -M arrest and subsequent caspase-mediated cell death. However, STLC-and docetaxel-treated PC3M cells have distinct fates: STLC induced a transient G 2 -M arrest, followed by polyploidy; in contrast, docetaxel-treated PC3M cells progressed to apoptosis after a transient G 2 -M arrest. Docetaxel-resistant LNCaP-derived (LDocR) cells respond to STLC in a similar manner to the parental cells. Although the docetaxel-resistant PC3M-derived (PDocR) cell line and its parental PC3M cells have similar GI 50 to STLC treatment, PDocR cells showed significantly more G 2 -M arrest and less apoptosis. Hence, although docetaxel-resistant prostate cancer cells remain responsive to Eg5 inhibition with STLC, there are key differences at the cell cycle level, which may have implication in future development.

A good molecular target for prostate cancer chemotherapy

“…4 In two recent studies involving Eg5 inhibition in prostate cancer, researchers found that docetaxel-resistant and non-resistant prostate cancer cell lines showed sensitivity to antisense oligonucleotide or S-trityl-Lcysteine. 16,17 In a previous study by some authors of the present study, the Eg5 inhibitor S(MeO)TLC was 10-fold more potent than the antisense oligonucleotide or S-trityl-Lcysteine for inhibition of cell proliferation and it was extremely specific toward Eg5. 18 In another recent study, S(MeO)TLC was shown to have potent anticancer activity in bladder cancer in vitro and in vivo.…”

A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor

“…34,35 These have revealed that docetaxel-resistant and non-resistant prostate cancer cell lines showed almost the same sensitivity to antisense oligonucleotide or STLC treatment. 34 In contrast to the antisense oligonucleotide and STLC used in those two studies, in our previous study, our target Eg5 inhibitor, S(MeO)TLC (20 mmol l 21 ), was at least 10-fold more potent for inhibition of cell proliferation, and was extremely specific to Eg5, without affecting other structurally and functionally related mitotic kinesins. 17 Furthermore, our current study confirmed that .…”

Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer

“…2). Kinesin motor proteins consist of a long coiled-coil stalk with a cargo-binding module at one end and globular motor domain (head) at the other (Wiltshire et al, 2010). Eg5 is a kinesin involved in bipolar spindle formation during mitosis.…”

“…Numerous Phase I and Phase II clinical trials have built a strong platform to bring Eg5 inhibitors to the clinical setting. One such inhibitor, S-trityl-L-cysteine (STLC), showed efficacy in Docetaxel-resistant prostate cancer cells and that STLC was not affected by P-glycoprotein (P-gp) upregulation (Wiltshire et al, 2010). A recent retrospective study identified Eg5 nuclear expression to be of clinical value as predictive marker of Docetaxel response in mCRPC patients, and a prognostic marker for hormone-naïve prostate cancer patients (Wissing et al, 2014).…”