AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Transl Res 1(4):393-405;2009

Original Article
Enhancing effectiveness of the MDR-sensitive compound T138067
using advanced treatment with negative modulators of the
drug-resistant protein survivin

Xiang Ling, Xiang He, Pasha Apontes, Felicia Cao, Rami G. Azrak, Youcef M. Rustum and Fengzhi Li

Departments of Pharmacology & Therapeutics and Cancer Biology, Roswell Park Cancer Institute, Buffalo, New
York 14263, USA, and Department of Obstetrics & Gynecology, Second West China Hospital, Sichuan University,
Sichuan 610041, China

Received June 20, 2009; accepted July 10, 2009; available online July 15, 2009

Abstract: Growing evidence indicates that the antiapoptotic protein survivin is a major factor of drug and radiation
resistance in cancer cells. However, application of this finding to therapeutic drug combination is largely
unexplored. In this study, breast cancer cells were used for treatment with anticancer compounds alone or in
combination. We report that T138067, a better drug against multiple drug resistance (MDR) tumor cells than taxol
(Shan et al., PNAS 96:5686-91,1999), induces survivin expression and consequently decreases its effectiveness
on the induction of cancer cell death. Treatment of breast cancer cells with T138067 induced survivin expression
in these cells while showing no effect on Bcl-2, indicating its specificity. Upregulation of survivin by T138067 was
concomitant with an increased drug resistance and associated with an increased phosphorylation of Akt and
Erk1/2 MAPK, and a decreased phosphorylation of p38 MAPK without affecting the phosphorylation of ErbB2.
Therefore, it is possible that inhibition of T138067-induced survivin expression by alternative approaches may
sensitize cells to T138067-induced cell death. We found that treatment of breast cancer cells with SN38, the
active metabolite of irinotecan, inhibits survivin expression. Intriguingly, inhibition of survivin expression by SN38
was more effective at a low concentration than at the high concentration, which makes SN38 a good survivin
modulator. Furthermore, in contrast with the decreased phosphorylation of p38 MAPK after T138067 treatment,
inhibition of survivin expression by SN38 was associated with an increased phosphorylation of the p38 MAPK,
suggesting opposing signals converging to survivin. Consistent with these observations, T138067 in
combination with SN38 strongly induced cell death in comparison with each drug alone. Similarly, sequential
combination of resveratrol, a component of red grapes that inhibits survivin expression, with T138067 also
provoked massive breast cancer cell death compared with T138067 alone. Together, these results highlight a
new concept that unique signaling cross talk converged to survivin may be considered for rational drug
combination in the clinic. (AJTR906005).

Key words: Survivin, T138067, SN38, irinotecan, Resveratrol, breast cancer cells

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Address all correspondence to:
Fengzhi Li, PhD
Department of Pharmacology and Therapeutics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, New York 14263
Tel:  (716)-845-4398
Fax: (716)-845-8857