Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

Abstract

Doxorubicin (DOX) is a well-known chemotherapeutic agent extensively applied in the field of cancer therapy. However, similar to other chemotherapeutic agents such as cisplatin, paclitaxel, docetaxel, etoposide and oxaliplatin, cancer cells are able to obtain chemoresistance that limits DOX efficacy. In respect to dose-dependent side effect of DOX, enhancing its dosage is not recommended for effective cancer chemotherapy. Therefore, different strategies have been considered for reversing DOX resistance and diminishing its side effects. Phytochemical are potential candidates in this case due to their great pharmacological activities. Curcumin is a potential antitumor phytochemical isolated from Curcuma longa with capacity of suppressing cancer metastasis and proliferation and affecting molecular pathways. Experiments have demonstrated the potential of curcumin for inhibiting chemoresistance by downregulating oncogene pathways such as MMP-2, TGF-β, EMT, PI3K/Akt, NF-κB and AP-1. Furthermore, coadministration of curcumin and DOX potentiates apoptosis induction in cancer cells. In light of this, nanoplatforms have been employed for codelivery of curcumin and DOX. This results in promoting the bioavailability and internalization of the aforementioned active compounds in cancer cells and, consequently, enhancing their antitumor activity. Noteworthy, curcumin has been applied for reducing adverse effects of DOX on normal cells and tissues via reducing inflammation, oxidative stress and apoptosis. The current review highlights the anticancer mechanism, side effects and codelivery of curcumin and DOX via nanovehicles.

Keywords: apoptosis; chemoresistance; curcumin; doxorubicin; nanodelivery; side effect.

Figure 1

The chemical structure of curcumin (a) and doxorubicin (b).

Figure 2

Schematic diagram of the proposed mechanism for promoting cellular uptake and overcoming MDR by Cur-pCB (poly(carboxybetaine)) -Dox in MCF-7/Adr cells. The nanosized feature of the zwitterionic antifouling micelles and endocytic pathway to bypass P-gp-mediated drug efflux led to high cellular uptake of the conjugated drugs that were released in the tumor cells of high GSH concentration. However, pCB-Dox and pCB-Cur can be delivered separately into different cells so that the drugs fail to play a synergistic role in inhibiting the MDR effect (a). By contrast, Cur-pCB-Dox codelivers Dox and Cur into the same tumor cells and results in synergistic effects of the two drugs (b). Merging images of cell uptake of pCB-Dox (left), pCB-Dox + pCB-Cur (middle) and Cur-pCB-Dox (right) in MFC-7/Adr cells (c). Cur: curcumin; Dox: doxorubicin; MDR: multidrug resistance; pCB: poly(carboxybetaine). Addapted with permission from [139].

Figure 3

Curcumin in promoting antitumor activity of DOX and reversing chemoresistance. ZnCM-SD, curcumin-Zn solid dispersion; EMT, epithelial-to-mesenchymal transition; TGF-β, transforming growth factor-beta; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; DOX, doxorubicin; TIMP-1, tissue inhibitor of matrix metalloproteinase-1; MMP-2, matrix metalloproteinase-2; EGCG, epigallocatechin gallate; AP-1, activator protein-1; NF-κB, nuclear factor-kappaB; P-gp, P-glycoprotein.

Figure 4

Curcumin in alleviation of adverse effects of DOX during chemotherapy. DOX, doxorubicin; cyt c, cytochrome C; NF-κB, nuclear factor-kappa B; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-a; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; SOD, superoxide dismutase; GSH, glutathione; CAT, catalase; ROS, reactive oxygen species; PiC, mitochondrial phosphate carrier.

Figure 5

(A) Side-by-side comparison of the tumors studied by μCT. Top row: Summation of intensity along the stack of CT slices (n slices ≈400) showing density variations and overall dimensions of the tumors. Bottom row: 3D photorealistic rendering of the tumors. (B) Tumor weight (* p < 0.05 vs. control and blank treatment groups). (C) Representative images of tumors excised at the end point of the study on day 15. Reprinted with permission from [194], ACS Publications, 2019.

Figure 6

Curcumin- and DOX-loaded nanovehicles in effective cancer chemotherapy. DOX, doxorubicin; GLUT1, glucose transporter 1; VEGF, vascular endothelial growth factor; P-gp, P-glycoprotein; miRNA, microRNA; MDR, multidrug resistance; TGF-β, transforming growth factor-β.