Abstract
5-Fluorouracil (5-FU) alone or in combination with other therapeutic drugs has been widely used for clinical treatment of various cancers. However, 5-FU-based chemotherapy has limited anticancer efficacy in clinic due to multidrug resistance and dose-limiting cytotoxicity. Some molecules and genes in cancer cells, such as nuclear factor kappa B, insulin-like growth factor-1 receptor, epidermal growth factor receptor, cyclooxygenase-2, signal transducer and activator of transcription 3, phosphatase and tensin homolog deleted on chromosome ten and Bcl-2 etc. are related to the chemoresistance and sensitivity of cancer cells to 5-FU. The activation of these molecules and genes expressions in cancer cells will be increased or decreased with long-term exposure of 5-FU. Curcumin has been found to be able to negatively regulate these processes. In order to overcome the problems of 5-FU, curcumin has been used to combine with 5-FU in cancer therapy.
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Introduction
5-Fluorouracil (5-FU) is a fluoropyrimidine analogue and the main mechanistic actions of anticancer activity are via inhibiting the activity of thymidylate synthase (TS) and DNA synthesis and repair by directly incorporating its metabolites into DNA and RNA of cancer cell (Noordhuis et al. 2004). 5-FU was widely used alone or in combination with other anticancer drugs for the treatment of colorectal cancer (Rossi et al. 2007), breast cancer (Yao et al. 2014), liver cancer (Cao et al. 2014; Cheng et al. 2012), pancreatic cancer (André et al. 2004), esophageal cancer (Liu et al. 2015) and gastric cancer (Mayr et al. 2012) etc. However, the application and efficacy of 5-FU-based chemotherapy are severely limited in clinic due to dose-limiting toxicity to the patients and multidrug resistance (MDR) in cancer cells, which is related to the over-expressions of TS (Peters et al. 2002; Wang et al. 2007). nuclear transcription factor (NF-κB, Gupta et al. 2010), cyclooxygenase-2 (COX-2, Sobolewski et al. 2010), human epidermal growth factor receptor (EGFR, Molinari et al. 2009), insulin-like growth factor 1 receptor (IGF-1R, Pollak 2008), and MDR gene 1 encoding transporter P-glycoprotein (P-gp) etc. NF-κB is activated by some stimuli such as inflammatory cytokines, bacterial products, reactive oxygen species, phorbol esters and other molecules through the phosphorylation and degradation of IκB kinase (IKK) and then the activated NF-κB increases the transcription of the target genes (Beg and Baldwin 1993; Prasad et al. 2010). Numerous studies have indicated that NF-κB was a major downstream effector of chemoresistance of various therapeutic drugs and NF-κB activation was closely related with the development of MDR (Chen et al. 2010; Mongre et al. 2015; Bonavida and Baritaki 2011). In addition, NF-κB regulates the expressions of a number of gene products, such as survivin, Bcl-xL, Bcl-2, COX-2, CyclinD1, P53 and Fas, which are related to carcinogenesis and apoptosis of cancer cells (Bassères and Baldwin 1993; Cao et al. 2015; Li et al. 2015a; Tsai et al. 2015). When cancer cells are exposed to 5-FU for a long time, the expressions of P53, Bax and Bcl-2 are dysregulated, which also lead to MDR (Li et al. 2015d; Wang et al. 2013a; Manoochehri et al. 2014; Tang et al. 2016). COX-2 is an inducible enzyme and overexpressed in several cancer cells such as breast, colorectal, gastric, and prostate cancers compared to normal tissues and COX-2 overexpression is related to the development and progression of cancer (Singh et al. 2005; Sobolewski et al. 2010; Cheng and Fan 2013). EGFR and HER2 belonging to human epidermal growth factor receptor family mediate the proliferation, differentiation, migration and invasion of cancer cells through a variety of signaling pathways and have become important targets of anticancer drugs (Ciardiello and Tortora 2008; Molinari et al. 2009). Insulin-like growth factor 1 receptor (IGF-1R), a transmembrane glycoprotein with the activity of tyrosine kinase, is related to the development and progression of cancer (Pollak 2008, 2012). The abnormal activities of EGFR, HER2 and IGF-1R could lead to MDR (Chen et al. 2015a, 2000; Dallas et al. 2009). Activation of P-gp is an important cause for MDR (Li et al. 2015c). Some studies indicated that the anticancer efficacy of 5-FU was increased when its dose was increased. Unfortunately, the cytotoxicity was significantly increased to normal cells, thus, induced unacceptable toxicity to the patients (Tang et al. 2012; Polk et al. 2013). In order to overcome these problems, an ideal strategy is to combine 5-FU with other anticancer drugs with different mechanistic action.
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, C21H20O6, MW 368.37 g/mol] is a natural compound extracted from the rhizome of zingiberaceae plants. Curcumin had been used as a food additive for centuries (Yuan et al. 2012). Recently, numerous studies have proved its potential effects on prevention and treatment of many types of cancer (Perrone et al. 2015). In addition, it was found that the combination treatment of curcumin with anticancer drugs may overcome MDR to increase anticancer efficacy and reduce cytotoxicity such as 5-FU (Shakibaei et al. 2013), paclitaxel (Zhan et al. 2014; Dang et al. 2015), gemcitabine (Ali et al. 2010; Kanai et al. 2011), oxaliplatin (Howells et al. 2011; Ruiz de Porras et al. 2016), doxorubicin (Chen et al. 2013; Lv et al. 2016), cisplatin (Chen et al. 2015b; Waseem et al. 2014) and so on. On the other hand, curcumin had little toxicity itself and didn’t increase the toxicities of other anticancer drugs, therefore, making it a good candidate for combination therapy.
Anticancer activity of curcumin
Curcumin has exhibited potential preventive and therapeutic effects such as antiinflammation, antioxidant, antirheumatism, reduced cardiovascular events, liver protection, and especially anticancer (Deodhar et al. 1980; Kiso et al. 1983; Miriyala et al. 2007; Qadir et al. 2016; Chen et al. 2017b; Mise Yonar et al. 2017). Curcumin has been widely used in prevention and treatment of various cancers including colorectal, gastric, breast, liver, esophageal, prostate, lung, brain cancers, and leukemia in preclinical studies (Perrone et al. 2015; Taverna et al. 2015; Tong et al. 2016; Ali et al. 2017; Wang et al. 2017).
The anticancer activities of curcumin were closely related to a variety of mechanisms such as cancer cell development, proliferation, transformation, invasion, metastasis and angiogenesis by affecting transcription factors, cytokines, chemokines, reactive oxygen species (ROS), COX-2, NF-κB, tumor necrosis factors (TNF), matrix metalloproteinase (MMPs), signal transducer and activator of transcription (STAT) and protein kinase B (Akt) etc. (Lev-Ari et al. 2006; Anand et al. 2007; Shankar et al. 2008; Shehzad et al. 2010; Shiri et al. 2015) and the proposed scheme is illustrated in Fig. 1.
Schematic model of the multiple signaling targets of curcumin in cancer cells. The solid lines indicate upregulation and the imaginary lines indicate downregulation
In addition, previous studies have shown that curcumin was able to reverse MDR through various mechanisms including antiproliferation, apoptosis induction, blocking cell cycle arrest, suppression of epithelial-mesenchymal transition (EMT) of cancer cells and so on (Zhou et al. 2011; Saha et al. 2012; Roy and Mukherjee 2014; Wang et al. 2014b; Rajitha et al. 2016). Curcumin also can reverse MDR by decreasing the expression and function of P-gp and promoting the activation of caspase-3 (Limtrakul et al. 2004; Tang et al. 2005; Lu et al. 2013; Oliveira et al. 2015). PI3K/Akt/mTOR, as one of the main cell signaling pathways, is involved in the proliferation, survival, metabolism and motility of cells and often activated in cancer cells (Fang et al. 2012; Gonzalez-Angulo and Blumenschein 2013). Its activation is related to the development of MDR in cancer cells (Sui et al. 2012). Activated PI3K can translate phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-triphosphate (PIP3) to phosphorylate Akt and further stimulate Akt-mediated activation of downstream targets including Bcl-2 family members, tuberous sclerosis complex 2 (TSC2) and mouse double minute 2 homolog (Mdm2, Massihnia et al. 2016). Furthermore, PTEN could negatively regulate this process by dephosphorylating PIP3 to inhibit the activation of PI3K/Akt/mTOR signaling pathway (Zhang et al. 2015). Studies also showed that curcumin could suppress the expression of P-gp via inhibition of the PI3K/Akt/NF-kB signaling pathway to reverse MDR (Choi et al. 2008). Cells undergoing EMT showed a similar feature to cancer stem cells (CSCs) with same drug resistance phenotypes (Singh and Settleman 2010; Wang et al. 2010). Studies showed that curcumin is an effective agent in treatment of esophageal cancer and exhibited potent cytotoxicity in a dose-dependent manner in all six tested cell lines, the inhibitory effect of curcumin not only eliminated cancer cells but also targeted CSCs against esophageal cancer cells (Almanaa et al. 2012). Study showed that curcumin upregulated EMT to reverse MDR (Suresh et al. 2016). Persistent activation of STAT3 was frequently detected in the majority of human cancer cells and tumor tissues (Bromberg et al. 1999; Bowman et al. 2000). Some studies showed that curcumin and its analog could reverse MDR via inhibiting the expression of STAT3 (Selvendiran et al. 2011; Kumar et al. 2014).
Extensive research from in vitro cell culture and in vivo animal models has shown that curcumin can sensitize various tumors to different chemotherapeutic agents such as 5-FU, paclitaxel, doxorubicin, vincristine, melphalan, butyrate, cisplatin, vinorelbine, gemcitabine, oxaliplatin, and etoposide etc. (Goel and Aggarwal 2010).
Taken together, curcumin enhances the therapeutic efficacy and reduces the toxicity of 5-FU, the combination of curcumin and 5-FU has been widely used to treat various cancer cells by enhancing the sensitivity and reverse the MDR induced by 5-FU. Therefore, this paper will review the synergistic combination of curcumin and 5-FU in the treatment of colorectal, breast, esophageal, gastric, liver, pancreatic and nasopharyngeal cancers and possible associated molecular mechanisms (as shown in Fig. 2) from the literature. So far, there are only two reports for randomized clinical trials of the combination of curcumin with 5-FU-based therapy (FOLFOX: 5-fluorouracil, folinic acid and oxaliplatin) in patients with colorectal cancer (James et al. 2015; Irving et al. 2015).
Schematic model of the molecular mechanisms of 5-FU combined with curcumin associated with anticancer effect. (When prolonged exposure to 5-FU, the activation of TS was enhanced, thereby leading to attenuate inhibit the death of cancer cell. The activated TS also could activate NF-κB to further inhibit the cell death. However, curcumin could inhibit the activation of TS, p-IKK and COX-2 to enhance the cancer cell death. Both 5-FU and curcumin could reduce the activation of STAT to enhance the cancer cell death. 5-FU could also activate PI3K, then, induced phosphorylation of AKT to stimulate the AKT-mediated activation of the Bcl-2 family members to inhibit apoptosis (cell death). Curcumin could reduce the activation of PI3K and AKT to enhance the cell death. In addition, the activation of PTEN could negatively regulate the activation of AKT to enhance the cell death
The synergistic combination of 5-FU and curcumin in cancer therapy
Colorectal cancer
Colorectal cancer is one of the most common cancers and the third leading cause of cancer death in the United States (Siegel et al. 2014). 5-FU alone or in combination with other chemotherapeutic drugs is widely used for the treatment of colorectal cancer (Inoue et al. 2006; Adamsen et al. 2007; Xu et al. 2016). However, MDR was developed in many patients with colorectal cancer during the course of chemotherapy with 5-FU-based regiments (Murakami et al. 2000; Körber et al. 2013). The problem was partly overcome by increasing the dose of 5-FU but high doses of 5-FU would lead to severe toxicities in patients and the treatment has to be discontinued (Eskandari et al. 2015; Vincenzi et al. 2015). Studies have found that the combination of 5-FU and curcumin may be an effective treatment regimen for the patients with colorectal cancer to overcome drug resistant and reduce cytotoxicity induced by 5-FU.
Direct genetic evidence showed that COX-2 plays a key role in tumorigenesis of colorectal cancer in heterozygous Apc Δ716 knockouts mice (Taketo 1998). Curcumin could reduce the risk of carcinogenesis and development of colorectal cancer by inhibiting COX-2 (Goel et al. 2001; Chen et al. 2006). Studies by Du et al. (2006) showed synergistic inhibitory effects of curcumin in combination with 5-FU on cell growth of human colon cancer HT-29 cells by significantly reducing the expression of COX-2 compared to each drug alone. Studies of curcumin in combined with FOLFOX (50 µM 5-FU and 1.25 µM oxaliplatin) significantly enhanced the cell growth inhibition of colon cancer HCT-116 and HT-29 cells to prevent the emergence of chemo-surviving cells by reducing the activation of EGFR, HER-2, IGF-1R and AKT and the expression of COX-2 and cyclin-D1 (shown in Figs. 3, 4) (Patel et al. 2010). Toden and colleagues carried out experiments with growth proliferation and apoptosis assays in parental and 5-FU resistant colorectal cancer cells and found that the combination of curcumin and 5-FU enhanced proliferation inhibition and cell apoptosis in both cells but 5-FU alone was ineffective against 5-FU resistant cells, the mechanism for curcumin sensitizing 5-FU-related chemoresistance in 5-FU resistant cells was through suppression of EMT (Toden et al. 2015). Moreover, the same group further demonstrated that curcumin sensitized 5-FU to inhibit tumor growth in vivo in a xenograft mouse models (Toden et al. 2015).
Reproduce with permission from Patel et al. (2010)
a Proportion of chemo-surviving HCT-116 cells following 48 h of treatment with FOLFOX (50 µM 5-FU and 1.25 µM oxaliplatin) by MTT assay. b Levels of activated (tyrosine phosphorylated) forms of EGFR, HER-2, IGF-1R, and downstream mediators AKT, and COX-2 in chemo-surviving HCT-116 cells by Western-blotting.
Reproduced with permission from (Patel et al. 2010)
a Growth inhibition of chemo-surviving HCT-116 and HT-29 cells treated with FOLFOX alone or in combination with curcumin (25 and 50 µM) for 96 h compared to media-treated cells (control). b The levels of activated growth factor receptors EGFR, HER-2, IGF-1R, and downstream mediators AKT, as well as COX-2, in chemo-surviving HCT-116 cells following treatment with FOLFOX alone or in combination with curcumin (25 and 50 µM), compared to media-treated cells (control). *P < 0.001 compared to control.
Shakibaei and colleagues showed that curcumin potentiated the chemosensitivity of 5-FU in 5-FU resistant colon cancer cells by down-regulating NF-κB activation and NF-κB-regulated gene products and enhanced 5-FU-induced expression cleavage of pro-apoptotic proteins (caspases 8, 9, and 3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins (Shakibaei et al. 2013, 2015). The same group also found that 5-FU activated NF-κB/PI-3K/Src pathway leading to the development of MDR to 5-FU, whereas curcumin down-regulated this activation to reverse MDR of 5-FU through inhibiting IKK activation and IκBα phosphorylation (Shakibaei et al. 2014). Studies showed that pre-treatment of curcumin was able to chemosensitize 5-FU and to reverse MDR in resistant MMR-deficient human colon cancer cells (Shakibaei et al. 2014). In addition, curcumin chemosensitized 5-FU by suppressing the expression of the multidrug resistance protein 1 (MRP1) and P-gp in resistant human colon cancer cells (Lu et al. 2013). Study showed that the anticancer effects of the combination of curcumin and 5-FU loaded thiolated chitosan nanoparticles were enhanced against on colon cancer cells in vitro and improved the bioavailability of the drugs in vivo than the free combination of curcumin and 5-FU (Anitha et al. 2014a. b).
Furthermore, a phase I clinical trial of curcumin in combination with FOLFOX in 12 colorectal cancer patients with inoperable liver metastases has been conducted, the dose escalation study showed that curcumin was safe and well-tolerated adjunct to FOLFOX chemotherapy in patients at doses up to 2 g daily (James et al. 2015). Another randomized control clinical trial has been conducted for the combination of curcumin with FOLFOX in 33 colorectal cancer patients with inoperable liver metastases to determine a target dose, side effects and antitumor efficacy, the results will be reported after completing the trial (Irving et al. 2015 ).
Breast cancer
Breast cancer is the most common cancer diagnosed among women and second most common cancer overall in the United States and worldwide (Torre et al. 2015). It is the second leading cause of cancer death in women only exceeded by lung cancer (DeSantis et al. 2014a). 5-FU alone or in combination with other chemotherapeutic drugs has been widely used for the treatment of patients with breast cancer clinically (Longley et al. 2003; Takahashi et al. 2014; Wu et al. 2015). However, 5-FU-based therapy has many limitations including drug resistance such as MDR and dose-limiting toxicity (Wang et al. 2013b). However, studies have found that the combination of 5-FU and curcumin may be an effective strategy for breast cancer treatment to overcome drug resistance and reduce toxicity induced by 5-FU.
In cancer therapy, MDR is developed in breast cancer cells when treating with chemotherapeutic drugs such as 5-FU because of the increase in the expressions of NF-κB, as the cancer cells usually reshape their survival signaling pathways. However, curcumin can inhibit NF-κB activity (Cao et al. 2015; Tsai et al. 2015), therefore, the combination of curcumin and 5-FU could reverse MDR of cancer cells to 5-FU treatment to increase therapeutic efficacy and reduce toxicity. Studies by Vinod et al. (2013) showed that the combination of curcumin (10 μM) and 5-FU (10 μM) could significantly increase the cell growth inhibition and enhance apoptosis compared to 5-FU alone in different breast cancer cells. Curcumin could sensitize the breast cancer cells to 5-FU through TS-dependent down-regulation of NF-κB, whereas 5-FU could up-regulate TS and NF-κB after long-term exposure (Vinod et al. 2013). In another study of curcumin combined with 5-FU against breast cancer cells and normal cells, curcumin enhanced cell growth inhibition of 5-FU against breast cancer cells but the LD50 value of 5-FU was increased from 28 µM to 200–300 µM with a 7 to 10-fold protection from 5-FU cytotoxicity by curcumin in normal breast cells, indicating that curcumin may enhance the chemotherapeutic effectiveness of 5-FU by protecting normal cells from reduced viability and thus permitting higher dosing or longer treatment duration (Ferguson and Orlando 2015). A recent study showed that the silk fibroin (SF) nanoparticles loaded with 5-FU and curcumin were more effective for inducing apoptosis of 4T1 murine breast cancer cells in vitro and antitumor activity in animal model in vivo compared to free curcumin and 5-FU via generation of cellular reactive oxygen species (ROS) (Li et al. 2016).
Esophageal squamous cell carcinoma
Esophageal cancer is the eighth most common cause of cancer-related death worldwide (Jemal et al. 2011; Torre et al. 2015). Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer. 5-FU-based therapy has been widely used in the treatment of patients with ESCC but the efficacy of treatment has been limited by drug resistance and toxicity (Kuwano et al. 2008; Wang et al. 2016). However, the combination of 5-FU and curcumin had been proved to reverse drug resistant and reduce toxicity induced by 5-FU in the treatment of ESCC in preclinical studies.
Studies have shown that curcumin promoted apoptosis and enhanced cell sensitivity to 5-FU in ESCC cells through inhibiting the NF-κB signaling pathways and the sensitizing effect of curcumin was via inhibiting the phosphorylation of IκBα and downregulating the expressions of Bcl-2 and cyclin D1 (Tian et al. 2008, 2012a, b). Furthermore, the combination of curcumin and 5-FU significantly reduced the tumor growth compared to curcumin or 5-FU alone in in vivo animal experiments with a nude mouse model of human ESCC xenograft (shown in Fig. 5). The same group also found that the suppression of NF-κB by curcumin resulted in decreased expression of anti-apoptotic protein Bcl-2 and cell cycle arrest by inhibiting the expression of cyclin D1 in ESCC Eca109 and EC9706 cells in vitro (Tian et al. 2012a).
Gastric cancer
Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death worldwide (Torre et al. 2015). 5-FU alone or in combination with other chemotherapeutic drugs was widely used in the treatment of gastric cancer (Qu et al. 2013; Jung et al. 2016; Mori et al. 2013; Shirao et al. 2013). However, drug resistance and toxicity induced by 5-FU and/or other drugs were the main obstacles for the effective treatment of patients with gastric cancer. However, curcumin combined with 5-FU may overcome the obstacles of MDR and toxicity induced by 5-FU in the treatment of gastric cancer.
Zhou et al. (2013) investigated the combined effect of curcumin and FOLFOX (0.1 µM 5-FU and 5 µM oxaliplatin) on cell growth inhibition of gastric cancer BGC-823 cells, and found that the anticancer effect of the combination was better than that of curcumin or the FOLFOX alone. The molecular mechanisms were related to apoptosis by increasing the expressions of Bax and caspase-3 and decreasing the expression of Bcl-2. Furthermore, an in vivo studies has found that the combination of curcumin and FOLFOX showed a stronger tumor growth inhibition against BGC-823 xenograft tumors than curcumin or FOLFOX alone and the inhibitory effect was related to apoptotic pathway including Bcl-2, Bax, caspases 3, 8, and 9 (Zhou et al. 2016).
The combination of curcumin and 5-FU showed enhanced cell death and a synergistic inhibition of survivin and STAT3 compared to each drug alone in gastric cancer AGS cells, thus, the effect of overcoming the chemoresistance of AGS cells was via down-regulating survivin and STAT3 during treatment of gastric cancer (Pandey et al. 2015). Koo et al. (2004) showed that curcumin combined with 5-FU had a stronger inhibitory effect on the growth of human gastric cancer AGS cells compared to curcumin or 5-FU alone, the greater cell growth inhibition induced by the combination was associated with blocking AGS cells in G2/M phase by curcumin. Another study by Kang et al. (2016) showed that curcumin could reverse the MDR of 5-FU in human gastric cancer SGC-7901 cells by downregulating the NFκB signaling pathway.
Liver cancer
Liver cancer is one of the most common cancers and the second fatal malignancy after pancreatic cancer, whose 5-year survival rate is as low as 16% (DeSantis et al. 2014b; Torre et al. 2015). In the past two decades, the mortality of liver cancer increased by more than 50% in the United States. In China, the rates of incidence and mortality of liver cancer are the highest in the world, especially in the Western region (Wei et al. 2014). Therefore, it is urgently needed to find an effective strategy to decrease the incidence and mortality of liver cancer. 5-FU alone or in combination with other chemotherapeutic drugs was widely used in the treatment of patients with liver cancer (Li et al. 2015b). However, MDR and toxicity of 5-FU limited its therapeutic efficacy. The combination of curcumin and 5-FU may overcome, at least in part, these problems to improve the outcome in treatment of liver cancer.
A study of the effects of curcumin (5, 10, and 20 mg/ml) in combination with 5-FU (at IC50) on cell growth inhibition and apoptosis with 5-FU resistant liver cancer Bel7402/5-FU cells by Cao et al. (2012) showed that the combination achieved significantly greater growth inhibition (21.47 ± 1.49, 27.10 ± 2.32 and 59.37 ± 2.45%), and higher apoptosis induction (30.92 ± 2.10, 44.87 ± 2.24 and 50.36 ± 2.58%) compared to curcumin growth inhibition: 6.74 ± 0.13, 9.31 ± 0.20 and 14.45 ± 1.02%, apoptosis: 12.03 ± 0.46, 13.54 ± 0.60, 18.14 ± 1.32%) and 5-FU (growth inhibition: 12.56 ± 0.87% and apoptosis: 25.59 ± 1.52%) alone, indicating that curcumin could reverse the drug resistance of Bel7402/5-FU cells. A study by Jing and Kong (2016) found that the inhibitory effects of 5-FU (7.5 μM) combined with curcumin (20 μM) on proliferation of HepG2 cells were stronger than 5-FU (7.5 μM) alone. The results also indicated that the combination of 5-FU and curcumin increased the level of PTEN and TLR4 and reduce the level of AKT to negatively regulate the PI3K/AKT signal pathway. In addition, the study showed that curcumin improve the anticancer effect of 5-FU by enhancing the sensitivity of liver cancer cells to 5-FU. Another study showed that the combination of SLN-curcumin and LDH-5-FU has stronger synergetic effect on apoptosis induction than the free combination of curcumin and 5-FU for the treatment of liver cancer SMMC-7721 cells (Zhu et al. 2013).
Pancreatic cancer
Pancreatic cancer is the fourth leading cause of cancer-related death worldwide and the incidence of pancreatic cancer has increased three times in last 10 years (Jemal et al. 2010; Siegel et al. 2013). Many patients diagnosed with pancreatic cancer were in the end-stage and postoperative recurrence rate was high, so chemotherapy is very important for the treatment of patients with pancreatic cancer. 5-FU alone or in combination with other chemotherapeutic drugs has been widely used in the treatment of patients with pancreatic cancer (Berlin et al. 2002; Hong et al. 2012; Li et al. 2014). However, chemotherapy of pancreatic cancer often failed resulted from the development of MDR and toxicity induced by 5-FU and/or other drugs (Hagmann et al. 2009; Wang et al. 2014a).
The combination of 5-FU and curcumin may be an effective strategy to overcome MDR and reduce toxicity induced by 5-FU to treat pancreatic cancer. Multidrug resistance-associated protein 5 (MRP5) conferred resistance to 5-FU by active efflux of drugs from the cell curcumin could enhance the anticancer effect of 5-FU by inhibiting the expression of MRP5 to overcome the resistance of 5-FU in pancreatic cancer cells (Li et al. 2011). A phase II clinical trial of curcumin in patients with advanced pancreatic cancer showed that oral administration of curcumin to the patients at 8 g daily was well tolerated and exhibited biological activity in some patients (Dhillon et al. 2008).
Nasopharyngeal cancer
Nasopharyngeal cancer is a rare type of head and neck cancer located at the nasopharynx and nasopharyngeal carcinoma (NPC) is by far the most common malignant tumor of the nasopharynx. NPC has a typical epidemiological characteristics and a high incidence in Southern China (Cao et al. 2011). The common treatment for NPC is radiotherapy and chemotherapy and the mean 5-year disease-free survival rats were 60–68% (Wei and Kwong 2010; Chapman et al. 2017; Ma et al. 2017). 5-FU alone or in combination with other chemotherapeutic drugs was widely used in the treatment of NPC and exhibited some efficacy (Chen et al. 2017a; Peng et al. 2017). However, drug resistance and severe side events induced by 5-FU and/or other drugs limited the long-term benefit of the treatment. Curcumin induced G2/M phase arrest and apoptosis in human NPC cells via apoptosis inducing factor and caspase-3-dependent pathways in vitro and inhibited proliferation of NPC through altering expression of proteins in the extracellular regulated protein kinase (ERK)-1/2 signaling pathway in a mouse model of tumor xenograft (Kuo et al. 2011; Xie et al. 2014). Therefore, curcumin in combination with 5-FU may reverse MDR and reduce toxicity induced by 5-FU in treatment of NPC (Wu et al. 2014).
The combination of 5-FU and curcumin significantly induced apoptosis compared to 5-FU and curcumin alone in NPC CNE-2Z cells via inhibiting the activity of NF- kB and enhancing the expression of Bax while inhibiting the expression of Bcl-2 (Wu et al. 2014).
Conclusion
5-FU-based therapy has been commonly used in the treatment of various types of cancer clinically. However, its therapeutic efficacy is limited due to drug resistance and severe toxicity. Curcumin is a natural compound with various biological and therapeutic effects and has displayed potential effects on prevention and treatment of different types of cancer. Numerous preclinical studies have shown that the combination of curcumin and various anticancer drugs may overcome drugs resistance to increase anticancer efficacy and reduce host toxicity in vitro and in vivo. Recently, curcumin in combination with anticancer drugs such as 5-FU has emerged as a hot research topic. In this paper, we reviewed the synergistic effects of the combination of curcumin and 5-FU in various cancers and associated possible mechanisms including activation or inhibition of a series of cell signaling pathways to enhance the sensitivity and reverse MDR in cancer cells response to 5-FU from preclinical studies. We hope it may help to shed some light for future clinical studies of the combination of curcumin and 5-FU or other therapeutic drugs in cancer therapy.
The prospect of the combination of 5-FU and curcumin in clinical application for cancer therapy seems to be promising, but also faces challenge. Therefore, it is necessary to evaluate the effectiveness and toxicity of the combination to access its feasibility in clinical practice. The safety and tolerability of curcumin alone in cancer patients have been well established in clinical studies (Dhillon et al. 2008; Storka et al. 2015). To the best of our knowledge, there are only two reports of curcumin in combination with standard care FOLFOX in patients with colorectal cancer clinically up to date (James et al. 2015; Irving et al. 2015). The dose escalation studiy showed that curcumin at doses up to 2 g daily was safe and well-tolerated adjunct to FOLFOX chemotherapy (James et al. 2015). Clinical trials of curcumin in combination with other anticancer drugs such gemcitabine (pancreatic cancer patients, Epelbaum et al. 2010; Kanai et al. 2011), docetaxel (breast cancer patient, Bayet-Robert et al. 2010) or docetaxel and prednisone (castration-resistant prostate cancer patients, Mahammedi et al. 2016) have been reported. However, the clinical application of curcumin in combination with 5-FU in cancer therapy still needs to be validated for antitumor efficacy and toxicity through a large number of clinical trials.
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Acknowledgements
This study was financially supported by the National Natural Science Foundation of China (81341124, 81101678), Science and Technology Support Project of Sichuan Province (2017JQ0013), Sichuan Provincial Human Resource and Social Security Department (2016-183), the Joint Fund of Sichuan Province, Luzhou City and Southwest Medical University (14JC0134, 14ZC0026, 14ZC0066), the Joint Fund of Luzhou City and Southwest Medical University [2015LZCYD-S09 (4/8)] and the Distinguished Professor Research Startup Funding (S. Cao) from Southwest Medical University.
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Wei, Y., Yang, P., Cao, S. et al. The combination of curcumin and 5-fluorouracil in cancer therapy. Arch. Pharm. Res. 41, 1–13 (2018). https://doi.org/10.1007/s12272-017-0979-x
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DOI: https://doi.org/10.1007/s12272-017-0979-x