Curcumin myths or wonders? A systematic analysis of in vitro studies

To the Editor: The medical literature abounds with data supporting antioxidant, anti-inflammatory, and anticarcinogenic properties of curcumin, an ethanol extract of turmeric, the powdered root of Curcuma longa. As a result, there is renewed scientific interest in curcumin’s potential to prevent and treat skin disease. For example, curcumin has been reported to hasten wound healing in rodent full-thickness cutaneous wound models. A phase II clinical trial examining oral curcumin treatment for patients with plaque psoriasis showed promise in some patients but a low response rate. The chemotherapeutic possibilities of curcumin for skin cancer are also being investigated. However, the literature is difficult to interpret and impossible to integrate. This letter is meant to elucidate in part why this is so, at least at the cell culture level. In cell culture studies curcumin has been reported to scavenge reactive oxygen species (ROS). However, other studies have shown that curcumin also possesses prooxidant effects. Banerjee et al. reported that curcumin acted as an antioxidant at low concentrations (<10 mM) and prooxidant at high concentrations (>10 mM). Curcumin has also been ascribed antiinflammatory properties via interactions with numerous molecular targets. For example, inhibition of proinflammatory enzymes and cytokines has been attributed to curcumin’s suppression of nuclear factor-kappa B (NF-KB) activation. Finally, curcumin has been credited with anticarcinogenic activity through numerous molecular targets, 40 of which lead to apoptosis. For example, in melanoma cells, apoptosis appeared to be induced through a Fas receptor/ caspase-8 pathway, independent of p53. In contrast, Mukhopadhyay et al. reported that curcumin inhibited the proliferation of squamous cell carcinoma cell lines by downregulating cyclin D1 expression. Since many results from the curcumin literature appear to be inconsistent, it has been impossible to make an overarching hypothesis as to curcumin’s mechanism(s) of action. Furthermore, it is difficult to discern whether any biological actions of curcumin result from direct inhibition of ROS or enzymes, or activation of specific receptors. The situation is further complicated by the fact that many papers did not completely delineate cell culture conditions. In fact, a Task Force on Good Cell Culture Practice has stated that “clear documentation of the systems used and procedures followed is mandatory, in order to permit the traceability, interpretation, and repetition of the work. ” We believe that clear delineation of cell viability, cell type, culture medium, presence or absence of serum/albumin, and time course of exposure is critical for cross-study comparisons for the following reasons. Curcumin has been shown to be cytotoxic to cells with evidence of decreased cell viability and growth inhibitory effects at levels as low as 5 mM. Thus, it is critical to ensure that any change in bioactivity is not due to the fact that cultured cells are dead or dying. Different cell types often respond differently to bioactives including curcumin. Some media contain antioxidants, e.g., pyruvate, phenol red, vitamin C or E, while others do not. Curcumin solubility in water varies depending on the presence or absence of albumin or serum, as curcumin is extremely hydrophobic but has a high affinity for albumin. Bioactivities of curcumin vary greatly by simply differing the time course of exposure. For example, Mackenzie et al. demonstrated that 2.5 mM curcumin caused significant decreased viability in Hodgkin and Reed-Sternberg KM-H2 cells after 72 hours whereas 25 mM curcumin decreased cell viability within a 24-hour incubation. Therefore, the inclusion of the aforesaid parameters were determined in curcumin cell culture studies obtained from a literature search using MEDLINE/PubMed databases for “cell” and “curcumin” from December 2006 through July 2009. Studies were limited to those published in the English language, and excluded review articles and editorials. A subgroup analysis of relevant papers was conducted on curcumin’s properties related to ROS using the five parameters from the initial analysis as well as two additional parameters: presence or absence of a potent antioxidant pyruvate in culture medium and cell density. Pyruvate is an extracellular scavenger of ROS, and Kim et al. recently demonstrated that increasing cell densities had greater resistance to oxidative stress. Two hundred fourteen papers met inclusion criteria for “cell” and “curcumin. ” Analysis showed that only 58% included complete information on all five experimental parameters (Figure 1). All studies included information about cell type; however, over one third of papers lacked or did not fully present cell viability data. Conclusions cannot be made about the anti-inflammatory, antiproliferative, or other effects of curcumin if the cytotoxicity is not measured due to the