PURPOSE: The purpose of this study was to evaluate the biological mechanisms of docetaxel (TXT) on salivary gland carcinoma. EXPERIMENTAL DESIGN: The effects of TXT on a spontaneous murine salivary carcinoma were determined. Proliferation, cell cycle regulation, connexin43 expression, gap-junctional intercellular communication, apoptosis, and Fas receptor (FasR) expression were measured. RESULTS: We characterized a spontaneous mouse salivary gland carcinoma (SGC1). SGC1 is a poorly differentiated carcinoma that originated from the parotid gland of a BALB/c mouse. SGC1 cells were cultured and found to be immortal past 30 passages. Initially, cells formed tumor nodules in severe combined immunodeficient (SCID) mice. Afterward, SGC1 cells that were subcultured from SCID tumors readily formed colonies in soft agar and were highly tumorigenic in SCID mice and immune-competent BALB/c hosts. Dose response for TXT with respect to growth suppression, G(2)-M cell cycle arrest, and apoptosis was found. Induction of apoptosis by TXT coincided with an increase in cell surface FasR expression. Up-regulation of FasR with lower doses of TXT rendered cells susceptible to FasR agonist antibody-mediated apoptosis. In the absence of TXT, anti-FasR antibodies were completely without effect, suggesting that TXT is critical for priming apoptosis mediated through the Fas pathway. In addition, gap-junctional intercellular communication was augmented by TXT in SGC1 cells concomitant with increased connexin43 expression and membrane localization. CONCLUSIONS: We have identified several novel targets of TXT that contribute to its antitumor activity in poorly differentiated salivary gland carcinoma. These results suggest that TXT may be appropriate for additional in vivo studies and clinical trials in patients with salivary cancers.
PURPOSE: The purpose of this study was to evaluate the biological mechanisms of docetaxel (TXT) on salivary gland carcinoma. EXPERIMENTAL DESIGN: The effects of TXT on a spontaneous murinesalivary carcinoma were determined. Proliferation, cell cycle regulation, connexin43 expression, gap-junctional intercellular communication, apoptosis, and Fas receptor (FasR) expression were measured. RESULTS: We characterized a spontaneous mousesalivary gland carcinoma (SGC1). SGC1 is a poorly differentiated carcinoma that originated from the parotid gland of a BALB/c mouse. SGC1 cells were cultured and found to be immortal past 30 passages. Initially, cells formed tumor nodules in severe combined immunodeficient (SCID) mice. Afterward, SGC1 cells that were subcultured from SCID tumors readily formed colonies in soft agar and were highly tumorigenic in SCIDmice and immune-competent BALB/c hosts. Dose response for TXT with respect to growth suppression, G(2)-M cell cycle arrest, and apoptosis was found. Induction of apoptosis by TXT coincided with an increase in cell surface FasR expression. Up-regulation of FasR with lower doses of TXT rendered cells susceptible to FasR agonist antibody-mediated apoptosis. In the absence of TXT, anti-FasR antibodies were completely without effect, suggesting that TXT is critical for priming apoptosis mediated through the Fas pathway. In addition, gap-junctional intercellular communication was augmented by TXT in SGC1 cells concomitant with increased connexin43 expression and membrane localization. CONCLUSIONS: We have identified several novel targets of TXT that contribute to its antitumor activity in poorly differentiated salivary gland carcinoma. These results suggest that TXT may be appropriate for additional in vivo studies and clinical trials in patients with salivary cancers.
Authors: Joseph D Sherrill; Melissa P Stropes; Olivia D Schneider; Diana E Koch; Fabiola M Bittencourt; Jeanette L C Miller; William E Miller Journal: J Virol Date: 2009-06-03 Impact factor: 5.103