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4. Curcumin Safety and Toxicity

In the systematic studies funded by the Prevention Division of the US National Cancer Institute (NCI) conducted in rats, dogs, or monkeys and at oral doses of curcumin up to 3,500 mg/kg-BW for up to 90 days, no adverse effects were observed []. In a preclinical study involving the administration of 2% dietary curcumin (approx. 1,200 mg/kg-BW) to rats for 14 days [] or in a study of 0.2% dietary curcumin (approx. 300 mg/kg-BW) administered to mice for 14 weeks, no toxicity was observed []. Furthermore, a reproductive toxicity study with the oral curcumin administration of up to 1,000 mg/kg-BW daily, no toxicity was observed in two successive generations in rats [].

4. Curcumin Safety and Toxicity

In a study performed in India, daily administration of 1,200–2,100 mg of oral curcumin to patients with rheumatoid arthritis for 2–6 weeks did not cause any toxicity []. In another study of high-dose oral curcumin by Cheng et al. in Taiwan, administration of 500, 1,000, 2,000, 4,000, and 8,000 mg of curcumin daily for three months to patients with preinvasive malignant or high risk premalignant conditions, no noticeable adverse effects were detected []. Lao et al. studied safety of curcumin in healthy volunteers using curcumin capsules (containing 75% curcumin, 23% demethoxycurcumin and 2% bisdemethoxycurcumin) with single escalating doses from 500 mg to 12,000 mg. Among 24 enrolled healthy subjects, seven developed adverse effects, including diarrhea, headaches, rashes and yellowish stools. All toxicities observed were of grade 1 and not related to the doses. In this study, the maximum tolerated dose could not be determined because more than 12,000 mg of curcumin is regarded as too bulky [].

4. Curcumin Safety and Toxicity

In a study performed in India, daily administration of 1,200–2,100 mg of oral curcumin to patients with rheumatoid arthritis for 2–6 weeks did not cause any toxicity []. In another study of high-dose oral curcumin by Cheng et al. in Taiwan, administration of 500, 1,000, 2,000, 4,000, and 8,000 mg of curcumin daily for three months to patients with preinvasive malignant or high risk premalignant conditions, no noticeable adverse effects were detected []. Lao et al. studied safety of curcumin in healthy volunteers using curcumin capsules (containing 75% curcumin, 23% demethoxycurcumin and 2% bisdemethoxycurcumin) with single escalating doses from 500 mg to 12,000 mg. Among 24 enrolled healthy subjects, seven developed adverse effects, including diarrhea, headaches, rashes and yellowish stools. All toxicities observed were of grade 1 and not related to the doses. In this study, the maximum tolerated dose could not be determined because more than 12,000 mg of curcumin is regarded as too bulky [].

4. Curcumin Safety and Toxicity

In a phase I clinical trial on oral curcumin in patients with advanced colorectal cancer in which the US NCI criteria were used to assess potential toxicity, curcumin was well tolerated at all dose levels up to 3,600 mg daily for up to four months []. Adverse effects related to curcumin consumption reported by patients in these studies were mainly gastrointestinal (nausea and diarrhoea). Two abnormalities were detected in blood tests in this trial, both possibly related to treatment: an increase in serum alkaline phosphatase level was observed in four patients (two NCI grade 1, and two grade 2); and three other patients had serum lactate dehydrogenase increases to >1.5 times the upper limit of normal. It is not clear whether these abnormal blood test results were related to the activity of the malignant disease in these patients or to treatment toxicity.

5.1. Animal Model Pharmacokinetics

Due to its poor systemic bioavailability after oral administration, many research groups have focused on ways to improve its bioavailability. Co-administration of oral curcumin with piperine, an alkaloid found in black pepper (Piper nigrum) and long pepper (Piper longa), appeared to increase serum concentrations of curcumin in rodents. In a study using high doses of oral curcumin (2,000 mg/kg) in rats, the investigators found that co-administration of piperine increased systemic bioavailability by as much as 154% []. The mechanism of this effect has not been elucidated yet.

Abstract

The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.

2. Immunomodulatory Effects of Curcumin

In some initial studies, curcumin supplementation showed no effect on the activity of natural killer (NK) cells in rats when given at doses of up to 40 mg/kg for up to five weeks []. However, in another study, Yadav et al. explored the immunomodulatory effects of curcumin and showed that this compound can increase NK cell cytotoxicity in vitro and that this effect can be further enhanced when curcumin was given along with IFN-γ treatment []. Increasing evidence indicates that curcumin exhibits its anti-inflammatory effects through the downregulation of NLRP3 inflammasomes []. Inflammasomes are multiprotein complexes that are responsible for innate immunity. The NLRP3, as a component of inflammasomes, can trigger immune response after detecting the products of damaged cells []. Curcumin can suppress NLRP3 inflammasome activation through regulation of the NF-κB signaling, leading also to suppression of IL-1β secretion []. For example, in malignant mesothelioma, curcumin has been found to exhibit its anticancer properties through regulation of signaling pathways affecting inflammasomes, such as IL-1 and NF-κB [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

3. Lung Cancer

Curcumin exhibits its therapeutic potential in lung cancer treatment by acting on the Wnt/β-catenin-dependent pathway in the human lung cancer cell line A549 []. Curcumin also suppresses the vascular endothelial growth factor (VEGF0 and NF-κB expression in the same cell line []. In addition, curcumin has been shown to inhibit the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells, which was followed by a decrease in the expression of the Notch 1 gene []. Curcumin has exhibited cytotoxicity against non-small-cell lung cancer (NSCLC) through inhibition of cell proliferation, increased apoptosis, and G2/M arrest. Curcumin also induces ROS production, thus activating the DNA damage signaling pathway [].