Doxorubicin enhances curcumin’s cytotoxicity in human prostate cancer cells in vitro by enhancing its cellular uptake

Abstract

Doxorubicin (DOX) is a widely used drug in cancer treatment. Despite its popularity, it suffers from systemic side effects and susceptibility to drug resistance. Curcumin (CURC), on the other hand, is a drug that recently gained popularity due to its wide range of biological activities, including anti-inflammatory and anti-cancer activities. Limitations to its clinical translation include its poor water solubility and the need for administration of high doses. Combinatory anti-cancer therapy has been proposed as a common approach to overcome one or more of these challenges. In this work, we propose a combinatory DOX and CURC anti-cancer therapy of prostate cancer cells in vitro. DOX and CURC were administered in the free drug and nanocapsule form, respectively. Cell size and complexity, cytotoxicity and apoptosis were studied by flow cytometry, MTT assay and sub-G1 quantification, respectively. Cellular uptake of CURC nanocapsules (CURC NCs) was quantified by fluorescence microscopy and high-performance liquid chromatography fluorescence detection. Results showed that in vitro treatment with CURC NCs in the presence of subtherapeutic concentrations of DOX, led to significant increase in prostate cancer cells (PC3) apoptosis and death. This was likely due to significantly enhanced CURC uptake by the cells. The study presents a good rationale for pursuing combinatory CURC/DOX therapy in pre-clinical tumor animal models in the near future.

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

“…Moreover, curcumin has been reported to act as a chemosensitizer for some clinical anticancer drugs (e.g., gemcitabine, paclitaxel and 5-fluorouracil, doxorubicin) and exhibits a synergistic effect in combination with other natural products (e.g., resveratrol, honokiol, epigallocatechin-3-gallate, licochalcone and omega-3), aspects that could be used as an effective strategy to overcome tumor resistance and reduce recurrence [ 108 , 119 , 120 ]. These observations therefore suggest that a superior therapeutic index may be achieved with curcumin when used in combination and could be advantageous in the treatment of some tumors.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Triptolide has strong liver and kidney toxicities, and when combined with curcumin, they exert synergistic anti-cancer effects in ovarian cancer, as well as reduce the side effects of triptolide [60]. In addition, adriamycin, sildenafil, 5-fluorouracil, irinotecan, doxorubicin, paclitaxel, sorafenib, Kruppellike factor 4, emodin, docosahexaene acid and apigenin are shown to exhibit synergistic effects with curcumin [61][62][63][64][65][66][67][68][69][70][71]. Similarly, copper supplementation significantly enhances the anti-tumor effects of curcumin in several oral cancer cells [72], while epigallocatechin-3-gallic acid ester (EGCG) increases the ability of curcumin to inhibit cell growth and induce apoptosis in human uterine leiomyosarcoma SKN cells [73].…”

A Modular Coassembly Approach to All-In-One Multifunctional Nanoplatform for Synergistic Codelivery of Doxorubicin and Curcumin

“…When compared with the conventional cocktail chemotherapy, the codelivery of multiple drugs in one NP system can realize the definitive delivery of a correct ratio of each drug and enable the controlled release in target site, prolong drug circulation half-life, accumulate at the tumors through enhanced permeation and retention (EPR) effect, and thus optimize the pharmacokinetics and biodistribution of drugs, achieving a more significant synergistic anticancer effect [ 14 , 15 , 16 , 17 ]. For example, the concurrent delivery of doxorubicin (DOX, one of the most active chemotherapeutics for cancer) and curcumin (CUR, a natural chemosensitizer with distinguishing abilities to inhibit P-gp overexpression and nuclear transcription factor NF-κB activation that are both closely linked to MDR) in one nanocarrier has been widely explored as an effective way to improve DOX treatment efficiency [ 18 , 19 , 20 , 21 ]. A variety of nanoparticulate delivery systems, such as liposomes or lipid NPs [ 21 , 22 , 23 , 24 ], polymeric micelles [ 25 , 26 , 27 ], prodrug NPs [ 28 , 29 , 30 ], as well as inorganic NPs [ 31 , 32 , 33 ], have been developed as codelivery vesicles for DOX/CUR.…”