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.