Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

Abstract

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 paclitaxelinduced cytotoxicity in vitro through downregulation of nuclear factor (NF)-jB 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-jB, 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-jB 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.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…Inhibition of PGE 2 -miR-21 signaling restored PTEN levels to baseline and decreased AKT activation , which was mirrored by a drop in cell viability due to the augmented induction of apoptosis . These findings have been validated by other reports that causally related curcumin-induced apoptosis in Cancer Pharmacology of Curcumin cancer cells to suppressed PGE 2 synthesis Lee et al, 2009;Sreekanth et al, 2011) and/or decreased AKT phosphorylation Elamin et al, 2010;Watson et al, 2010a;Prakobwong et al, 2011;Wong et al, 2011). c. Angiogenesis (H-VII). The angiogenic switch (Bergers and Benjamin, 2003) is primarily triggered by VEGF (Keck et al, 1989;Leung et al, 1989), the expression of which is upregulated in most human cancers (Ferrara and Davis-Smyth, 1997).…”

Staying a Step Ahead of Cancer

“…Curcumin inhibits proliferation and induces apoptosis in cancer cells via suppression of the AKT pathway , Sun et al 2010, Duarte et al 2010, Saini et al 2011, Prakobwong et al 2011, Zanotto-Filho et al 2011, Sreekanth et al 2011. Moreover, it decreases cell growth via inactivation of NF-κB, preventing DNA binding, nuclear translocation, and p65 phosphorylation.…”

Liposomal curcumin inhibits Lewis lung cancer growth primarily through inhibition of angiogenesis

“…This result may be associated with the inhibition of proliferation and the induction of apoptosis and cell cycle arrest in endothelial cells in vitro. Liposomal curcumin has been reported to exhibit anti-cancer activity on colorectal cancer (19), prostate cancer (20), head and neck squamous cell carcinoma (21), and pancreatic (22) and cervical cancer (23). In this study, we revealed that liposomal curcumin inhibits tumor growth in the Lewis lung cancer mouse model primarily by targeting tumor angiogenesis.…”