Synergistic inhibition of tumor growth by combined treatment with the pan Bcl-2 inhibitor AT-101 and docetaxel in human cancer xenograft models

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The Bcl-2 family of proteins plays an important role in the resistance to current anti-cancer therapies and is associated with unfavorable clinical outcome. AT-101 is an orally active pan Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-w, Mcl-1) currently under clinical development in several Phase II trials. The objective of this study is to evaluate the effectiveness of combined treatment with AT-101 and docetaxel both in vitro and in vivo using androgen-independent human prostate cancer cells (PC-3) and non-small-cell lung cancer cells (A549).

Methods: Cell growth inhibition was measured using WST-based assays. The CalculSyn program was used to assess drug interaction by calculating the Combination Index (CI) value. In vivo, the ability of AT-101 to potentiate the anti-cancer effect of docetaxel in xenograft models using human NSCLC cells (A549) or prostate cancer cells (PC-3) was evaluated.

Summary: Strong synergy in vitro was observed with the combination of AT-101 and docetaxel in prostate cancer (PC-3, C.I< 0.8) and in NSCLC (A549, C.I. <0.9) cell lines. In vivo, combined treatment with AT-101 and docetaxel synergistically suppressed subcutaneous NSCLC A549 cells tumor growth compared with treatment with either agent alone. In the NSCLC A549 model, the combination of AT-101(15mg/kg, p.o., daily) and docetaxel (8 mg/kg, i.v., once weekly) showed anti-tumor efficacy with a T/C value of 13% whereas the single agent treatments were less effective (T/C value =54% for both AT-101 and docetaxel) (P<0.001). In the same model, a combination of AT-101 at 15 mg/kg and docetaxel (16 mg/kg) was more effective than either agent alone (T/C value of 12%, versus T/C=54% for AT-101 alone and 22% for docetaxel alone, respectively) (P<0.001). All animals treated had a significant tumor size difference between combination treatment and monotherapy groups and no significant toxicities were observed in combination as compared with monotherapy. Additional preclinical studies using other cancer models are underway. Preliminary studies have demonstrated significant tumor growth delay with the combination of AT-101 and docetaxel in the prostate cancer model (PC-3).

Our results demonstrate that AT-101significantly enhances the anti-tumor activity of chemotherapy and may represent a promising new anticancer agent with a novel molecular mechanism. Molecular targeted therapy with AT-101 may improve the outcome of current chemotherapy for human prostate cancer or NSCLC with Bcl-2, Bcl-xL and/or Mcl-1 overexpression.