The microtubule-targeting
antineoplastic agent,
paclitaxel, is highly efficacious against a wide spectrum of human
cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize
cancer cells to
paclitaxel can enhance the
therapeutic effect of this
drug. We have previously shown that
curcumin, a natural
polyphenol, enhances
paclitaxel-induced cytotoxicity in vitro through downregulation of nuclear factor (NF)-κB and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage
squamous cell carcinoma model using
3-methylcholanthrene (3-MC) and a xenograft model of human
cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of
curcumin and
paclitaxel induced a synergestic reduction in the
tumor incidence as well as
tumor volume of animals compared with the individual treatments of
paclitaxel or
curcumin, although
curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of
curcumin augments the antitumor action of
paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-κB, Akt and
mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and
metastasis. This study revealed for the first time that 3-MC-induced
tumorigenesis in mice is associated with a strong constitutive activation of NF-κB activity. Furthermore, we also observed that pre-exposure of
carcinoma cells isolated from 3-MC-induced
tumors to
curcumin potentiates
paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As
curcumin could effectively downregulate all these survival signals induced by
paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of
paclitaxel.