Curcumin as a Chemosensitizer in Conventional Chemotherapy: History
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Contributor:
Daniel L. Pouliquen
,
Koraljka Gall Trošelj
,
Ruby John Anto

Turmeric (Curcuma longa) was used for thousands of years in traditional Indian and Eastern Asian medicine. Its cultivation in the Middle East was documented since the 18th century BC in the gardens of Babylon, well before its transfer to Africa, mainly through Arabic influences. To reverse multidrug resistance, curcuminoids can be used in combination with many other drugs as chemosensitizer in cancer chemotherapy.

  • curcuminoids
  • curcumin
  • cancer
  • signaling pathways

1. Introduction

Turmeric (Curcuma longa) was used for thousands of years in traditional Indian and Eastern Asian medicine. Its cultivation in the Middle East was documented since the 18th century BC in the gardens of Babylon, well before its transfer to Africa, mainly through Arabic influences [1]. Finally spread to Europe thanks to Marco Polo, and then to America and Oceania via the international spice trade, it is one of the best examples of how the exchange of knowledge between different parts of the world benefited humankind in improving the health of millions of people. Among natural anticancer products, it also represents a fascinating and continuous link between past, present and future [1]. Its benefits as a food additive for the prevention of many diseases worldwide began to be documented through the report, in 1949, of the antibacterial action of its main component, curcumin [2]. However, a short report published in 1876 [3] demonstrated that a great portion of empirical knowledge accumulated over centuries in Asia was not fully valorized between these two dates. Nevertheless, its potential anticancer activity was originally demonstrated against the development of tumors in animals [4].The relief produced by a topical application of curcumin ointment in patients with external cancerous lesions was also revealed [5].
At the beginning of 2023, the number of publications related to the use of turmeric’s main phytochemical as an anticancer agent reached 7267 in the PubMed database. Although curcumin represents “the leading” molecule, a significant part of these articles refers to “curcuminoids” [6].The term also covers other plant secondary-metabolites belonging to the diarylheptanoids class [7], semi-synthetic structures such as prodrugs consisting of promoieties attached to the phenolic hydroxyl groups [8] and synthetic chemical molecules [9] that were initially produced for optimizing pharmacological potency [10]. Synthetic chemistry based on curcumin represents an exciting field of research, one that started with initial attempts: incorporating parts of the curcumin structure into an elaborate chemical scaffold, or trying to shorten or lengthen the aliphatic chain linking the two aromatic rings [11]. It has been developing since 2008 [11], and continues to grow [12].
Ten years ago, the diversity of inhibitory effects produced by these molecules on a multitude of molecular targets (e.g., enzymes, transcription factors and nucleic acids) and pathways involved in carcinogenesis and tumor progression started to be documented. The interest for curcuminoids in cancer research, with relation to diversity of targets and consequences, was explained by the different conformations they adopt to maximize these interactions, mainly through the keto-enol tautomer, flexible α, β-unsaturated β-diketo dimer, and the terminal o-methoxyphenolic groups [13].

2. Curcumin as a Chemosensitizer in Conventional Chemotherapy

2.1. Chemosensitization: Need of the Hour

Natural products from diverse sources encompass a unique arena of chemical space that overlaps extensively with pharmaceuticals which are not found in synthetic chemical libraries. These natural compounds have been evaluated for a long time for their ability to selectively target different kinds of ailments, including cancer. Most of the anticancer drugs used in chemotherapy are natural-product-derived compounds [14][15]. Nowadays, most of the currently available chemotherapeutics fail to accomplish their expected outcome. Upon prolonged exposure to the chemotherapeutics, the emergence of inherited and acquired chemoresistance due to the upregulation of major survival signals is regarded as the main cause for this drawback. Combination chemotherapy is currently used for various cancer types, and this approach is more effective, compared to single-agent treatment [16]. Multidrug resistance (MDR), the ability of tumor cells to develop resistance to a broad range of structurally and functionally unrelated drugs, is also a major hindrance in the success of combination chemotherapy. Apart from the classic mechanisms of MDR development (over-expression of drug efflux pumps and increased activity of DNA repair machinery), alterations at the level of apoptosis control serve as a crucial mechanism for the induction of drug resistance [14]. Increasing the dosage of the drug can certainly help in evading the condition, but serious side effects limit the success of the clinical outcomes of chemotherapy. It may also lower patients’ quality of life, and, in some cases, even result in discontinuation of chemotherapy [17].
Thus, chemosensitization can be a choice that absolutely matches the need. Chemosensitization can be defined as a process by which a non-toxic compound of either natural or synthetic origin sensitizes the cancer cells to a cytotoxic therapeutic agent without affecting the efficacy of the same. This has an added advantage of minimizing the dosage of the chemotherapeutic and thereby decreasing the side effects. Additionally, this strategy is more economical, considering the cost of currently available chemotherapeutic drugs, especially in the case of developing countries, where the rate of cancer incidence is relatively high. Since chemoresistance is a tightly regulated process under the control of multiple survival pathways, the inhibition of any single molecule may not be sufficient to circumvent the phenomenon. Hence, compounds that can simultaneously modulate multiple survival-signaling pathways might provide a better therapeutic outcome than that of individual inhibitors. Several phytochemicals have been shown to modulate multiple pathways involved in chemoresistance and, hence, are assumed to be of better chemosensitizing efficacy.

2.2. Curcumin: The Celebrity among Nutraceuticals

From ancient days onwards, Indian and Chinese traditional medicine have made use of combinations of medicinal herbs. Among those, flavonoids are a large subgroup of the family of natural polyphenolic compounds, which are mostly the part of secondary metabolism in plants [18][19]. Most of the plant polyphenols, including curcumin, resveratrol, genistein, quercetin, epigallocatechin gallate (EGCG), luteolin, apigenin, chrysin, tannic acid, etc. are dietary compounds which are part of our day today diet. Amongst the wide range of natural polyphenols, curcumin is the most-studied natural compound, with perfect documentation of its therapeutic effect in a large number of disease conditions, including cancer [20][21].
Curcumin is well known for its chemopreventive [22][23][24][25][26][27][28][29], as well as chemosensitizing [14][30][31][32][33][34][35][36][37][38], efficacy against cancer, together with anti-inflammatory, antioxidant and antibacterial activities [39][40]. 

2.3. Molecular Targets of Curcumin as a Chemosensitizer

Curcumin exerts its anticancer effect through targeting various regulatory molecules, including protein kinases, transcription factors, receptors, enzymes, growth factors, cell cycle, and apoptosis-related molecules, as well as microRNAs. Several reports have shown the effects of curcumin on variety of key molecular signaling pathways, such as NF-ĸB, MAPK, PI3K/Akt/mTOR, JAK/STAT, Wnt/β-catenin, etc. [41][42]. It also possesses modulatory effects on the apoptotic, metastatic and cell cycle pathways involved in cancer development and progression [32]. The major molecular targets that regulate the chemosensitizing efficacy of curcumin are depicted in Figure 1.
Pharmaceutics 15 01612 g002
Figure 1. Pleiotropic effects of curcumin relevant for its chemosensitizing activity.

2.4. Curcumin as a Chemosensitizer in Adjuvant Chemotherapy

Several in vitro, in vivo and clinical trials have shown the chemosensitizing efficacy of curcumin in combination with current chemotherapeutic drugs. Curcumin has been reported to potentiate the antitumor effects gemcitabine via downregulation of COX-2 and phospho-extracellular signal-regulated kinase1/2 (ERK1/2) levels in pancreatic adenocarcinoma cells [43], as well as through the inhibition of gemcitabine-induced NF-κB and its downstream targets, in an orthotopic model of pancreatic cancer [44]. A phase II clinical trial also evaluated the effectiveness of the combination [45]. Studies have shown that curcumin sensitizes breast cancer cells to 5-FU-mediated chemotherapy through the inhibition of 5-FU-induced upregulation of thymidylate synthase (TS), both in vitro [46] and in vivo [33], irrespective of the receptor status. It was also shown that the antitumor effects of paclitaxel could be enhanced by curcumin in cervical cancer cells through the downregulation of paclitaxel-induced activation of NF-κB, Akt and Bcl-2 [30][37][38]. The ability of curcumin to augment the antitumor effect of capecitabine in human colorectal cancer by modulating cyclin D1, COX-2, matrix metallopeptidase 9 (MMP-9), VEGF and C-X-C chemokine receptor type 4 (CXCR4), has been assessed by using an orthotopic mouse model [47]. Curcumin has also been also shown to sensitize prostate cancer cells to the cytotoxic effect of 5-FU through a tp53-independent cell-cycle arrest and the downregulation of constitutive NF-κB activation [48]. Curcumin enhances the cytotoxic effects of 5-FU and oxaliplatin in colon cancer cells through the downregulation of COX-2 and the modulation of EGFR and insulin-like growth factor 1 receptor (IGF-1R) [49]. Both in vitro [50] and in vivo [51] data shows that curcumin-mediated inhibition of NF-κB activation enhances the sensitivity of prostate cancer cells to TRAIL-induced apoptosis. It has been reported that the combination of curcumin and doxorubicin could enhance the sensitivity of breast cancer cells through inhibition of ABC subfamily B member 4 (ABCB4) activity [52]. Downregulation of IAPs by curcumin has also been reported to enhance the effect of cisplatin in hepatic cancer cells [53]. Recent reports have also suggested that the combination of curcumin and paclitaxel could inhibit the ALDH-1 and paclitaxel-induced Pgp-1 expression in breast cancer cells. The combination resulted, in treated cells, in upregulation of Bax, caspase-7, and caspase-9, along with downregulation of Bcl-2 expression [54]. Curcumin has been shown to inhibit the FA/ BRCA pathway, and it sensitizes ovarian cancer cells to cisplatin-induced apoptosis [55]. It has shown that inhibition of HER2 and reduction of NF-κB activation by the combination of curcumin and its derivatives with doxorubicin enhances the toxicity of doxorubicin in resistant breast cancer cells [56]. Moreover, doxorubicin-induced over-expression of major proteins, including vimentin, β-catenin, p-AKT, p-Smad2 and p-GSK3β, Snail and Twist, which are involved in EMT and metastases of TNBC cells, were found to be downregulated through the suppression of TGF-β and PI3K/AKT signaling pathways [57]. Studies have illustrated that co-treatment with curcumin and cisplatin sensitizes breast cancer cells to cisplatin through the activation of the autophagy pathway. In treated breast cancer cells, the key mechanism underlying the curcumin-mediated chemosensitization was found to be the downregulation of CCAT1 expression and inactivation of the PI3K/Akt/mTOR pathway [58]. Several reports have indicated the ability of curcumin to reverse the cisplatin resistance in lung cancer. It has been shown that curcumin enhances sensitivity of human NSCLC cell lines toward cisplatin treatment through influencing a Cu-Sp1-CTR1 regulatory loop [59]. Curcumin reverses cisplatin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms [60]. Results from a very recent study also showed that curcumin sensitizes NSCLC cells to cisplatin-mediated cell death through activation of the ER stress pathway [61]. Tan and Norhaizan showed that a combination of camptothecin and curcumin-loaded cationic polymeric nanoparticle increased intracellular drug concentrations and synergistic effects of the drugs in colon-26 cells [62]. Curcumin has been shown to prevent liver cancer stem cells’ growth through inhibition of the PI3K/AKT/mTOR signaling pathway [63]. Furthermore, curcumin-based nanoparticles and curcumin-tagged antibodies were reported as promising therapeutic strategies to overcome resistance in brain tumors [64].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15061612

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