Curcumin and Bladder Cancer: Comparison
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The most common type of bladder cancer (BC) is urothelial carcinoma arising from stratified epithelium-urothelium. Layers of cells are arranged into strata perched on the basement membrane (BM), then on lax connective tissue, followed by the muscular part of the bladder wall. The breeching of the urothelial BM, facilitated by an aberrant activation of matrix metalloproteinases (MMP) is particularly perilous. Inhibition of activation of these proteinases constitutes a logic opportunity to restrain progression. Recent studies revealed significant anticancer potential of natural phytochemicals. Especially, curcumin has emerged as a one of the most promising phytochemicals and showed its efficacy in several human malignancies.

  • bladder cancer
  • basement membrane proteins
  • phytochemicals
  • curcumin
  • matrix metalloproteinases

[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]1. Biological Properties of Curcumin in Cancer Processes

For ages, herb- and plant-derived medicines have been a staple in therapy, even without exact knowledge of contained active components or the mechanism of action. Several extracted pure substances, their derivatives, or synthetic equivalents are widely used even today. Contemporary molecular biology and analyses of cell signaling pathways reveal mechanisms of action, and potentially new pharmacological uses of known old nutrients present in common food. Natural ingredients from food (nutrients, nutraceuticals, phytochemicals) or their derivatives can replace or synergistically reinforce the action of current medicines when combined with standard therapeutic regimens [1][47].
New findings provide a very promising perspective of selected compounds as substances with high therapeutic potential for human malignancies. The potential is promising for 2000 plants, each containing numerous molecules, which are under laboratory and clinical evaluation now [2][48]. Despite their demonstrated anti-cancer efficacy, the precise molecular mechanism of activity is not clearly established [3][49]. The activity of phytochemicals tested in vitro on experimental cell lines differs from effects observed on clinical settings for the multiplicity of additional interactions and interdependencies between different cells and tissues [4][50]. Last but not least, relatively inexpensive and easily available natural phytochemicals and derivatives may be difficult to compete with expensive, extolled drugs.
An example of a nutrient exerting potent biological activity is curcumin, currently the most intensively tested phytochemical. Widely used as a food additive, it shows a lack of any toxicity. [5][6][7][8][51,52,53,54]. Its curative properties, as used in traditional Asian medicine for the treatment of nonhealing wounds and gastrointestinal diseases, present safety even in high doses [9][10][55,56]. Recently, curcumin gained attention due its antioxidant, antiatherosclerotic, anticancer (antiproliferation, anti-invasive, and antimetastatic) activity [11][34].
Curcumin is an active compound from the turmeric rhizome Curcuma longa. Raw or dried-pulverized turmeric is commonly used as a spice in Asia [9][12][55,57]. Up to 235 bioactive compounds have been extracted from turmeric. The most abundant are curcuminoids: curcumin, demethoxycurcumin, and bisdemetoxycurcumin, in a proportion 7:2:1, respectively [13][58]. Nowadays, curcumin is used in food processing as a spice and as a natural pigment. Its chemical structure was first described by Polish chemists in 1910 [14][59]. Chemically, curcumin is a polyphenol-diferuloylmethane: (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptane-3,5-dione) [6][9][52,55]. It has two constitutional isomers: enol and b-diketone tautomeric forms. The former exists predominantly in solutions, the latter is important for free radicals’ scavenging ability [9][15][55,60].
The degradation of the basement membrane—a prerequisite for tumor invasion—is mediated mainly by MMP-2 and -9. Abundant data present that the anticancer and antimetastatic effect of curcumin is linked to inhibition of MMP activity. This potential of curcuminoids is dose- and time-dependent, as demonstrated on in vitro cultured cells [9][16][55,61]. In addition to downregulation of MMPs, curcumin upregulates expression of tissue inhibitors of MMP, especially TIMP-2. Further, curcumin counteracts metastasis formation by the restriction of cancer cell adhesion molecules, allowing for binding to ECM [17][62]. Curcumin-related decreased expression of MMP-2 and -9 also inhibits angiogenesis [18][63]. The mechanisms of such an impressive range of activities have not been fully elucidated yet. Diverse anticancer and antioxidant properties seem to have common crucial elements linking these activities. Curcumin inhibits cell signaling pathways, and hampers expression of several cancer-related genes (for instance, COX-2, TNF, cyclin D1). Several papers present that its main impact point focuses on nuclear factor kappa B (NF-κB) and STAT pathways regulating the above genes (Figure 2) [9][55]. NF-κB is a ubiquitous inducible transcription factor present in all animal cells, and is the pivotal element of the pathway transmitting extracellular signals into the nucleus to stimulate the expression of numerous genes. Thus, curcumin appears to be a master regulator of almost all cellular processes involved in cell proliferation, survival, and response to external factors. It binds to promotors of targeted genes, and activates their transcription [19][64]. Substances which can control and modulate NF-κB, in turn, can control and modulate the function of genes and the cell’s fate. Curcumin has properties to suppress the activation of NF-κB (Figure 2). Binding any ligand to the cell surface receptor induces a specific kinase, IKK, which phosphorylates, and thus, inactivates an inhibitor of NF-κB-IκB. The promoters of MMP genes have binding sites for NF-κB. Then, NF-κB dimerizes and translocates to the nucleus to promote transcription of any given gene for cell membrane-bound metaloproteinase MT1-MMP. MT1- MMP proteolyse pro-MMP-2 into active MMP-2. Curcumin interrupts this pathway by blocking IκB kinase (IKK), and thwarts MMP-2 activation, and subsequent extracellular matrix degradation and invasion [20][65]. Concurrently, other NF-κB dependent genes and their products (MMP2,9, cyclin D1, CoX-2, Ras, iNOS, bcl-2, bclxl) are downregulated and suppressed, so cell proliferation and migration are inhibited. A similar protecting mechanism of curcumin has been described for restricting NF-κB benzopyrene (a cigarette smoke compound)-related activation of genes expression in selected lung carcinoma cell lines [21][66]. Additionally, curcumin through bcl-2/bclxl-related inhibition of NF-κB pathways activates caspase-mediated cell death [21][22][66,67]. An alternative pathway of curcumin suppression on MMP-2 runs through the Akt serine/threo-nine protein kinase axis, as proved by curcumin’s anti-lymphangiogenic effect on an experimental line of lymphatic endothelial cells (Figure 1) [22][67].
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Figure 1. Multidirectional and multilevel preventive and inhibitory effects of curcuminoids on oncogenesis, with a special emphasis on induction and progression of bladder cancer, and its subsequent development. Prevention and inhibition of neoplastic transformation and progression is achieved through induction of apoptosis, inactivation of cancer-related transcriptional pathways (nuclear transcription factors and related oncogenes), cancer cell DNA damage (direct and indirect), inactivation of extracellular carcinogens, downregulation of growth factors, activation of cancer-suppressing genes, suppression of angiogenesis, and metastatic niche formation. Consecutive boxes of the diagram group intra- and extracellular molecular targets of curcumin.
A probable mechanism of MMP inhibition relies on zinc ions locking through the metal-binding moiety of curcumin [9][10][55,56]. Another inhibitory mechanism of curcumin on MMP-2 and -9, and on proliferation signaling pathways is in the decreasing expression of extracellular signal-regulated protein kinase (p-ERK1/2), associated with cell proliferation and survival. A transcription factor regulator p-ERK1/2 is involved in signal transduction from the cell membrane to the nucleus [9][23][55,68]. A mammalian target of rapamycin (mTOR) pathways is a next target for curcumin inhibitory activity, and through the phosphatidylinositol 3-kinase/Akt/IkBk kinase axis, MMP-2 and -9 expression are also significantly suppressed [9][55]. Further, curcumin also selectively targets MMP2 by restricting expression of mRNA for MMP2 [24][69]. Curcumin-induced apoptosis was experimentally presented in prostate cancer cell lines as propagated through TNF-a-related apoptosis-inducing ligand (TRAIL).
Because NF-κB is a component of pro-inflammatory signaling pathway, and is involved in the production and release of inflammatory cytokines such as TNF-alfa, which, in turn, activate MMP, this mode of activity can also potentiate the antitumor properties of curcumin [25][70]. Tumor-infiltrating lymphocytes express upregulation of MMP-9, which, in turn, promotes neoplastic proliferation and invasion. Curcumin inhibits this trait by suppressing the cancer propagatory influence of cytokines excreted from the inflammatory transformed peritumoral extracellular matrix [26][71]. Further, decrease of MMP-2 expression, and an increase of TIMP-1 intensified antiproliferative and anti-invasive effects on a breast cancer cell line [9][26][55,71]. Another mechanism of indirect downregulation of MMPs expression relies on the ability of curcumin to suppress ECM inducer (EMMPRIN, CD147), crucial for cancer cell adhesion, tumor invasion, and metastasis. This cell membrane glycoprotein is abundant in cancer cells, and stimulates production, secretion, and activation of MMPs by cells (monocytes and macrophages) present in tumors surrounding the EC stroma. CD147 also binds MMP at the cell surface, and helps the cell to directly degrade surrounding pericellular ECM and further invasion [27][72]. Curcumin inhibition of MMP-2 and -9 activity also restores blood–brain barrier integrity, as reported for cerebral ischemic injury [11][34]. Another positive involvement on vascular pathology has been presented. Curcumin reduces activity of MMP-2 and -9 during plaque formation, and suppresses NF-κB and MMP-9 expression in vascular smooth muscle cells, contributing to atherosclerosis formation (Figure 1) [9][55].
Unfortunately, important issues related to the use of curcuminoids still remain unresolved. Clinical application of curcumin is hampered by its somewhat unfavorable biological properties. Bioavailability of curcumin is low because of its limited water solubility at acidic and neutral pH, resulting in poor intestinal absorption, and also its rapid degradation by glucuronidation in the intestinal wall and in the liver [7][28][53,73]. To overcome barriers related to the limited bioavailability of curcumin, a number of modifications to the administration or its chemical structure have been tested. Research has been aimed at improving the absorption of curcumin, on slowing its metabolism, and on linking it with other substances to achieve synergy; thus, enhancing their therapeutic activities. Co-administration with piperine enhances intestinal absorption, and diminishes biodegradation (glucuronidation) of curcumin, and thus, increases curcumin bioavailability up to 20× [5][51]. Curcumin-piperine formulation as a nanoparticle is a useful solution, and has been extensively tested. [29][30][74,75]. The combination with phosphatidyl-choline increases oral absorption of curcumin in humans 5-fold [9][55]. Another formulation combines both molecules into liposomes as one stable water-soluble delivery system [5][51]. Experimental delivery systems couple curcumin with chemotherapeutics [31][32][76,77]. Liposomal formulation with polyethylene glycol, and complexes with phospholipids or dextrin have been tested for intravenous administration [5][51]. The addition of hydrophilic groups considerably improves the solubility of curcumin [30][31][32][33][75,76,77,78]. To make curcumin more relevant for bladder cancer treatment, intravenous infusion or intravesical instillations have been tested for the prevention of recurrence after tumor resection or BCG-therapy [32][33][77,78]. Other solutions enhancing curcumin absorption consider metal complexes, magnetic microspheres, or solid-lipid nanoparticles, which can be delivered straight to the targeted organs [29][30][31][74,75,76]. Published clinical trials present that complexing cyclodextrin with curcumin significantly improves intestinal absorption of curcuminoids [30][33][75,78]. Such commercial preparations are now available (brand name: Meriva, Curarti) [34][35][79,80].
Another field of clinical application is the synergistic activity of curcumin with existing anticancer agents. Co-administration of curcumin and paclitaxel significantly reduced expression of metalloproteinase-2, and decreased paclitaxel side effects in a PC3 xenografted prostate cancer model. In effect, such a formulation is proposed for hormone-refractory prostate cancer (HRPC) [9][55]. The synergistic action of gemcitabine plus curcumin has been presented in in vivo and in vitro models of pancreatic cancer [36][81]. In pancreatic cancer cell lines, inhibition of proliferation and apoptosis were substantially increased. Mice models of pancreatic cancer presented a significant reduction of tumor volume, suppression of NF-κB regulated genes (for cyclin D1, Bcl-2, BclxL, COX-2, matrix metalloproteinases, VEGF), and decreased microvessel density (Figure 1) [36][81].
Structural modifications of the curcumin molecule may facilitate its bioavailability, and increase treatment potential. New chemical analogues of curcumin form a very promising group of anticancer drugs. An analog FLLL32 blocks binding of transcription factors to DNA; induces its degradation; decreases VEGF, MMP-2, survivin expression; and promotes apoptosis in an experimental human osteosarcoma cell line [37][82]. Another analog is formulated by altering aromatic moiety to increase water solubility, metal binding, and MMP inhibition [4][50]. Contemporarily, a few dozen curcumin derivatives and dibenzoyl analogs have been tested for possible antioxidant, antiproliferative, and anti-inflammatory efficacy [4][50]. Hydrazinocurcumin, another synthetic curcumin derivative, significantly inhibited expression of MMP-2 and -9 by inhibition of the STAT3 signaling pathway as presented in breast cancer cell lines [9][55]. A very promising modification of curcumin aims at improving the binding of zinc ions. A novel MMP inhibitory formulation combines tetracyclines with curcumin [4][50]. Tetracycline molecules contain diketonic moiety, which binds zinc ions, and thus, may inhibit zinc-containing MMPs irrelevantly to antibacterial properties [8][54]. Similar metal-binding moieties contain curcumin molecules, and thus, complexing tetracycline with curcumin will combine and increase their inhibitory effect on MMPs by the zinc-binding properties of both being formulated into a new compound [8][10][54,56].

2. The Rationale for Curcumin Application in Bladder Cancer as a Potential Factor Limiting the Progression of the Disease

The characteristic clinical feature of bladder cancer is its propensity to recur and progress. Approximately three-quarters of cases are initially confined to the urothelium, not crossing the BM, as non-muscle-invasive cancer (NMIBC). The remaining one-quarter of cases manifest as muscle-invasive neoplasm (MIBC). A five-years recurrence rate of NMIBC reaches 70%, and one-third of them will progress to invasive MIBC. At the stage of invasive disease, the prognosis is much worse, as 15% patients will develop metastases [4][38][39][50,83,84]. The response rate for combined chemotherapy such as MVAC (methotrexate + vinblastine + doxorubicin + cisplatin) reaches up to 20%; however, 60% of patients do not respond to the treatment [5][51].
Surgical treatment of NMIBC is complemented by intravesical immunotherapy or chemotherapy with attenuated tuberculosis mycobacteria (BCG) or cytostatics (mitomycin), respectively. The aim of this treatment is to prevent the disease from becoming the muscle-invasive form. Immunotherapy and chemotherapy show efficacy, but a significant percentage of patients do not respond to such treatment, and develop severe adverse reactions. Therefore, research is targeted at the development of innovative high-potential medications replacing or enhancing the above adjuvant therapies to significantly improve the effectiveness of treatment [4][40][50,85]. Unfortunately, existing and innovative systemic and intravesical drugs are characterized by a high rate of side effects, along with a failure to achieve expected outcomes. Over 30% of patients do not respond to intravesical BG treatment [40][85]. Intravesical chemotherapy (mitomycin, epirubicin, thiotepa) causes local and systemic toxicity, whereas its actual therapeutic efficacy is limited [39][84]. Up to 50% of patients respond to adjuvant chemotherapy, but almost all are affected by its toxicity [38][40][83,85].
Natural plant-derived products have emerged as valuable alternatives with proven nontoxicity and suitability for the prevention and treatment of a number of ailments. Yet, only recently, meticulous research has revealed the complexity of the molecular mechanisms of action of commonly used nutraceuticals. Curcumin is an extensively tested nutrient for its proven, virtually unlimited therapeutic qualities. Its beneficial effects have been shown for a number of human malignancies during several clinical trials. A small series of tests have been carried out on bladder cancer. As bladder cancer therapy is the most capital-intensive among all cancer therapies, it is reasonable to reach for inexpensive, but effective, substances complementing and amending surgery—still accepted as the contemporary essential form of the treatment [41][42][86,87]. Existing clinical and laboratory experiments present multidirectional anticarcinogenic activities of curcumin on bladder cancer as monotherapy, or synergistically potentiating other chemotherapeutics. Moreover, experimental data presents curcumin bioactivity on all stages of carcinogenesis both intra- and extracellularly at concentrations of at least 40 μmol/L [41][86]. A number of experiments were conducted in vitro on experimental cell lines to explain intracellular mechanisms of curcumin activity [40][85]. Yet, despite having obtained many data, the exact mechanisms by which curcumin executes observed effects have not been fully explained [41][42][86,87].
Clonal assays presented and proved that curcumin is lethal to BC cell lines inducing apoptosis and arrest of the cell cycle in both G1/S and G2/M phases [40][43][85,88]. Curcumin also downregulated expression of essential antiapoptotic proteins (Bcl-2, Survivin, NF-κB) in parallel with upregulation of proapoptotic mediators (Bax, p53, caspase 3). These effects are stronger than those caused by cisplatin alone [43][44][45][88,89,90]. The apoptotic effect of gemcitabine and paclitaxel was intensified when co-administered with curcumin [36][40][44][81,85,89]. Concurrently, curcumin exhibits chemopreventive properties, due to in-vitro-presented inhibition of intracellular pathways activating external chemical carcinogens [39][84].
Still, intravesical BCG immunotherapy remains the most effective method of treatment of bladder cancer. Prevention of tumor recurrence and of transition from non-muscle invasive to invasive tumor is the main goal of such therapy. Several in vitro and in vivo studies presented prominent synergistic effects of co-administration of BCG and curcumin [32][33][77,78]. This beneficial phenomenon is multidirectional through influence on different cellular signaling molecules. Curcumin potentiates proapoptotic effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by upregulation of its main DR5 membrane receptor [46][47][91,92]. Because BCG acts mainly through stimulation of the expression of TRIAL by neutrophils, co-administration with curcumin will enhance and intensify the BCG-induced immune response in bladder cancer [32][33][46][77,78,91]. On experimental cancer cells lines, the percentage of apoptotic cells ranged from 43% to 74% for BCG alone and BCG+curcumin, respectively [46][91]. The ineffectiveness of BCG-therapy observed in a subset of patients can be explained by the TRAIL resistance of tumor cells, related to constitutive (over)activation of nuclear factor NF-κB [46][91]. As curcumin suppresses NF-κB and further expression of dependent genes, its addition to BCG can reverse this resistance, and potentiate apoptosis [47][92].
Another pathway contributing to BCG-therapy failure is the overexpression of proapoptotic protein Bcl-2, which inhibits TRAIL-induced apoptosis. As described, curcumin effectively inhibits Bcl-2 and enhances tumor cells death [48][93]. In vitro assays proved that expression of proliferation marker cyclin D1 decreased by 50% after treatment with BCG alone, and up to 90% concomitantly with curcumin [46][91]. A proapoptotic response was additionally supported, and intensified by the formation of reactive oxygen species under curcumin influence [40][41][85,86]. Several other cellular pathways are modulated by curcumin, such as an inhibition of nitric oxide synthase, tyrosine kinases, transcriptional factors c- jun/AP-1, arachidonic acid pathways, COX activity, and many more. Wnt/Beta-catenin signal transduction pathways are also targeted by curcumin by downregulation of catenin, thus, affecting crucial metastasis EMT induction in bladder cancer cells [41][86]. This activity overlaps with the inhibition of MMP-2 and -9 expression, also involved in EMT processes. Indeed, the expression of mesenchymal markers (vimentin, N-cadherin) decreases in the presence of curcumin in a dose-dependent manner, whereas the expression of epithelial differentiation markers (E-cadherin) increases. This indicates that curcumin suspends bladder cancer cells in an epithelial, polarized phenotype; and restricts ″mobile″ mesenchymal features, hampering cancer cell migration, bladder cancer invasiveness, and further metastasis [49][94]. Curcumin also suppresses beta-catenin overexpression in bladder cancer cells, and thus, reverses metastatic potential and migration of bladder cancer cells in a dose-dependent manner [41][42][86,87].
The above data and other published studies suggest that the suppression of the NF-κB pathway is most likely essential for the multidirectional activity of curcumin (anti-inflammatory, anti-proliferatory, anti-invasive, anti-angiogenic) [44][46][47][89,91,92]. This mechanism was depicted in a previous part of this paper, and was proved on experimental bladder cancer cell lines [44][89]. The evidence shows that several others pathways associated with PI3K/AKT/mTOR, ERK1/2-signaling, insulin receptor substrate-1, insulin-like growth factor-2, and trophoblast cell surface antigen-2 related to bladder carcinogenesis are also affected by curcumin [4][5][50,51]. Data from in vitro experiments are confirmed by in vivo studies. In animal models of human bladder cancer, both xenografts and chemically induced curcumin inhibited cancer cell implantation, tumor growth, and metastasis [41][86]. These effects were observed after gavage, and after intravesical instillation. To overcome poor intestinal absorption, alternative modes of application have been tested. In line with intravesical administration, intraperitoneal and intravenous injections proved to be systematically effective and safe in a rat bladder cancer model [39][84]. All above studies show that curcumin is an effective modality in the prevention of NMIBC bladder cancer recurrence and progression, both as a sole agent and as a synergistic additive chemosensitizer for existing therapies [4][5][50,51].
Intravesical instillations of curcumin in experimental mouse bladder cancer models resulted in tumor necrosis and a significant reduction of tumor size, but with no effect on the number of tumors per bladder [44][89]. The combination of curcumin and BCG appeared to be more effective than BCG or curcumin alone [46][91]. In addition to the impact on existing tumors, curcumin inhibited implantation of free cancer cells in a bladder cancer murine model through the influence on integrin adhesion receptors [50][51][95,96]. A beneficial additive effect has been presented for intravesical or intratumoral or oral administration of curcumin concurrent with standard intravesical administration of BCG, with doses up to 8000 mg/day [46][91]. Even though only a few such studies have been published, evidences suggest a high therapeutic capacity of curcumin in bladder cancer, and place curcumin as possible integral part of therapy [4][5][50,51]. The synergy of BCG and curcumin is reflected in cellular molecular events, such as in a decrease of cell proliferation proteins (Ki67, cyclin D1, c-myc), anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin), and pro-angiogenic proteins (CD31, VEGF), and the inhibition of epigenetic controllers (HDAC) [5][51].
Curcumin also potentiates therapeutic effects, and alleviates side effects of bladder cancer adjuvant chemotherapy. It increases therapeutic efficiency, and reverses tumor resistance to gemcitabine [52][97]. The combination of oral curcumin with intraperitoneal cisplatin resulted in an increased therapeutic efficiency of chemotherapy, and an increased reduction of tumor size in mouse models [53][98]. This synergistic effect can be explained by the induction of reactive oxygen species-related activation of proapoptotic pathways, and the inhibition of antiapoptotic pathways [53][98]. Concomitantly, curcumin alleviates cisplatin-related nephrotoxicity.
Acute kidney injury is the most common severe side effect of cisplatin-based therapy. Nephrotoxicity is related to a series of dysfunctional cellular metabolic pathways which pathologically intensify renal inflammatory processes, along with devastating oxidative stress, necrosis, and apoptosis of proximal tubular epithelial cells (PTEC) [5][54][55][56][51,99,100,101]. Cisplatin directly and/or indirectly induces upregulation of key molecules involved in those pathways, among others: TNF-α, p53, Fas ligand/receptor system, COX-2, caspases, and nuclear transcription factor-kappa B (NF-κB). These pathways are interlinked through common molecules [54][55][56][99,100,101]. Overexpression of TNF-α activates humoral and cellular inflammatory processes, and induces the generation of reactive oxygen species, leading to renal damage. P53 activates Bax-related proapoptotic pathways, and impairs Bcl-2- and Bcl-xL-related antiapoptotic pathways. Also, the Fas ligand/receptor apoptotic system is pathologically induced by cisplatin-upregulated p53 [54][55][56][99,100,101]. Cisplatin-related activation of transcription factor NF-κB, together with upregulated p53, stimulates pathways suppressing nephroprotective cytokine HNF1β, and also through the promotion of TNF-α synthesis [54][56][99,101]. Such interactions induce renal tubular cells apoptosis and necrosis, resulting in acute kidney injury. Further, epithelial damage attracts an influx of immunocompetent cells, with subsequent aggressive renal damage. Studies revealed that selective suppression of the above molecules alleviates cisplatin-related tubular epithelium dysfunction and renal injury. Existing nephroprotective strategies (cimetidine, mannitol, amifostine, celecoxib, etc.) are not always effective [5][54][55][51,99,100]. Curcumin directly and indirectly blocks the aforementioned molecules and involved pathways (see Figure 1). Laboratory experiments clearly present that curcumin reduced acute kidney injury in mice, and downregulated the pro-apoptotic cisplatin-related response in renal tubular cells [54][56][99,101]. This curcumin-associated reno-protective effect is achieved precisely by targeting key multifunctional cytokines, such as p53, NF-κB, Bax, and the others mentioned above. Therefore, curcumin appears to be an important renoprotective complementary and supportive agent for cancer chemotherapy [54][99].
Immunologic escape of the tumor has also been modulated by curcumin through inhibition of expression of programmed cell death ligand 1 (PDL1) on both bladder cancer cells and tumor-infiltrating lymphocytes, as proved by in vivo and in vitro experiments [5][51]. Also, a clinical trial presented that curcumin intensified patients’ immunologic response by stimulation of interferon-gamma production, and the propagation of T- helper lymphocytes and cytotoxic NK cells [5][51].
To fully exploit anti-PDL1 activity of curcumin, a few studies have been conducted. The combined application of curcumin molecules and anti-PDL1 antibodies was tested in a bladder tumor mouse model [5][51]. This construct targets the programmed cell death protein (PD-1) receptor of lymphocytes. One clinical trial on patients with gynecological carcinomas combining pembrolizumab (clinically approved anti-PD1 receptor antibody) with RTG therapy and curcumin food supplementation (with additional vit. D, lansoprazole, aspirin, cyclophosphamide) was conducted to elevate the proportion of response for a PD-1-blockade + radiotherapy treatment regime [57][102].

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