Context "Mitocans" destabilise mitochondria, causing apoptogenic factors’ release. "Mitocans" include alpha-TOS, thought to be toxic only for cancer cells. Aims 1) To verify alpha-TOS effects on pancreatic cancer (PC) and normal cell growth; 2) to ascertain whether the combination of non toxic alpha-TOS and 5-FU dosages causes cancer cell death; 3) to obtain insights into caspase3 activation. Methods Five PC cell lines and normal monocytes were cultured in 1% and 10% FCS, without or with alpha-TOS (5, 10, 20, 50, 100, 200 and 500 µM), for three days. Two cell lines were treated with 5-FU (0.0001 mM) and alpha-TOS (20 and 50 µM) alone or in combination. Cell growth (XTT) and caspase3 activity (colorimetric method) were measured. Results In 1% FCS, 20 µM or more alpha-TOS inhibited PC cell growth (F=57.9, P<0.001, BxPC3; F=91.8, P<0.001, Capan1; F=54.4, P<0.001, MIAPaCa2; F=48.9, P<0.001, Panc1; F=110.6, P<0.001, PSN1). In 10% FCS the same effect was obtained with higher alpha-TOS dosages (100, 200 and 500 µM). Alpha-TOS dose dependently inhibited monocytes’ growth in 1% FCS (F=110.5, P<0.001); 100 µM or more were effective in 10% FCS (F=83.8, P<0.001). PSN1 growth (F=658, P<0.001), not Capan1 (F=63, P<0.001), was delayed after non toxic 5-FU and alpha-TOS combination. PSN1 and monocytes caspase3 activity doubled after 5-FU, alpha-TOS or their combination (0.036 to 0.066 pmol/min/µg protein). Conclusion PC cells are sensitive to high alpha-TOS dosages, not safe for normal cells. Treatment with safe alpha-TOS and 5-FU dosages caused only a transient PC cell growth inhibition. Alpha-TOS activated caspase3 both in neoplastic and normal cells. Our findings highlight the limitations of this molecule for "in vivo" applications and the need for searching new compounds.

Analogues of vitamin E epitomised by alpha-tochopherol succinate (alpha-TOS) for pancreatic cancer treatment: in vitro results induce caution for in vivo applications

GRECO, ELIANA;PADOAN, ANDREA;FOGAR, PAOLA;ZAMBON, CARLO-FEDERICO;PEDRAZZOLI, SERGIO;PLEBANI, MARIO;BASSO, DANIELA
2008

Abstract

Context "Mitocans" destabilise mitochondria, causing apoptogenic factors’ release. "Mitocans" include alpha-TOS, thought to be toxic only for cancer cells. Aims 1) To verify alpha-TOS effects on pancreatic cancer (PC) and normal cell growth; 2) to ascertain whether the combination of non toxic alpha-TOS and 5-FU dosages causes cancer cell death; 3) to obtain insights into caspase3 activation. Methods Five PC cell lines and normal monocytes were cultured in 1% and 10% FCS, without or with alpha-TOS (5, 10, 20, 50, 100, 200 and 500 µM), for three days. Two cell lines were treated with 5-FU (0.0001 mM) and alpha-TOS (20 and 50 µM) alone or in combination. Cell growth (XTT) and caspase3 activity (colorimetric method) were measured. Results In 1% FCS, 20 µM or more alpha-TOS inhibited PC cell growth (F=57.9, P<0.001, BxPC3; F=91.8, P<0.001, Capan1; F=54.4, P<0.001, MIAPaCa2; F=48.9, P<0.001, Panc1; F=110.6, P<0.001, PSN1). In 10% FCS the same effect was obtained with higher alpha-TOS dosages (100, 200 and 500 µM). Alpha-TOS dose dependently inhibited monocytes’ growth in 1% FCS (F=110.5, P<0.001); 100 µM or more were effective in 10% FCS (F=83.8, P<0.001). PSN1 growth (F=658, P<0.001), not Capan1 (F=63, P<0.001), was delayed after non toxic 5-FU and alpha-TOS combination. PSN1 and monocytes caspase3 activity doubled after 5-FU, alpha-TOS or their combination (0.036 to 0.066 pmol/min/µg protein). Conclusion PC cells are sensitive to high alpha-TOS dosages, not safe for normal cells. Treatment with safe alpha-TOS and 5-FU dosages caused only a transient PC cell growth inhibition. Alpha-TOS activated caspase3 both in neoplastic and normal cells. Our findings highlight the limitations of this molecule for "in vivo" applications and the need for searching new compounds.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2277801
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