Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma.

Introduction

Mesothelioma features an aggressive tumor disease with increasing incidence associated with high mortality rates (median survival of ca. 1 year after diagnosis), poor prognosis and ca. 40.000 deaths per year worldwide [ 1 ]. Asbestos was identified as the most important carcinogen for mesothelioma development, and in combination with other factors (e.g., SV40 virus infection, genetic disposition such as BAP1 mutation or inactivation) asbestos promoted inflammation processes, enhanced EGFR, VEGFR, Akt, and Notch signaling as well as 5-LOX expression [ 2 , 3 ]. Asbestos-mediated cell necrosis released HMGB1 leading to an inflammation response in macrophages and mesothelial cells and to transformation of mesothelial cells [ 3 ]. Altered protein expression is often accompanied by altered levels of certain non-coding RNAs. Mesothelioma cell expression of miRNAs often differed from the expression profiles of non-malignant samples while circulating miRNAs were likewise determined in mesothelioma patients [ 3 , 4 ]. Various miRNAs can serve as prognostic factors, as potential therapeutic targets and as therapeutic agents [ 4 ]. Several miRNAs were shown to regulate oncogenes, apoptosis and/or vital signaling pathways [ 5 ]. In particular, drug-resistant cancer stem-like cells are strongly regulated by non-coding RNAs [ 6 ]. High expression of miR-21-5p, miR-221-3p, and the miR-17-92 cluster (miR-17-5p, miR-20a-5p) associated with drug resistance was observed from short survivors among malignant pleural mesothelioma (MPM, i.e., the most abundant mesothelioma disease) patients when compared with long survivors [ 7 ]. MiRNAs have also emerged as anticancer drugs and minicells called TargomiR, which are loaded with miRNA-16 mimic miRNA, displayed an acceptable safety profile and moderate clinical response in a clinical phase 1 trial with MPM patients which can be optimized in combination with other anticancer drugs [ 8 ]. Another class of non-coding RNAs dubbed long non-coding RNAs (lncRNAs) is ample in the genome, and lncRNAs have become of distinct importance for the understanding of cancer diseases as well [ 9 ]. Many lncRNAs are involved in vital cellular processes such as chromatin remodeling, gene regulation, inhibition of smaller miRNA molecules, and in the regulation of Wnt signaling [ [9] , [10] , [11] ].

Indeed, there are only very few treatment options for mesothelioma patients at the moment. The problematic location of the primary tumors near vital organs often render surgery and radiation therapy options while systemic platinum chemotherapy in combination with pemetrexed is given in most cases as first-line therapy of mesothelioma [ [12] , [13] , [14] ]. The antimetabolites gemcitabine and pemetrexed were thoroughly investigated in mesothelioma patients and feature valuable tools for MPM chemotherapy [ 15 ]. The combination of platinum complexes and pemetrexed with the VEGFR-inhibitor bevacizumab was recently identified as a superior first-line therapy of MPM when compared with the currently mostly applied platinum plus pemetrexed treatment [ 16 , 17 ]. This review provides an overview of the interactions of mesothelioma-relevant non-coding RNAs with the approved antimetabolites gemcitabine and pemetrexed. Various agents with known effects on non-coding RNA activity and expression were discussed which exhibited beneficial effects on gemcitabine or pemetrexed activity against mesothelioma diseases. This work thematically follows a review recently published in this journal about the role of non-coding RNAs concerning the efficacy of approved platinum-based drugs in mesothelioma [ 18 ].

Antimetabolites and their interactions with non-coding RNAs in mesothelioma

Gemcitabine and pemetrexed

Gemcitabine (Gemzar ® ) is an antimetabolite applied against a variety of solid tumors including cancers of the lung and the pancreas [ 19 , 20 ]. It is a deoxycytidine analog (2‘-deoxy-2‘,2‘-difluorocytidine-monohydrochloride) similar to the drug ara-C (cytosine arabinoside, cytarabine) ( Fig. 1 ) [ 21 ]. But in comparison to ara-C, the optimized drug gemcitabine exhibited increased membrane permeability, extended inhibition of DNA synthesis, and higher affinity to deoxycytidine kinase [ 21 ]. Upon activating phosphorylation in the cell, gemcitabine triphosphate featuring a competitive analog of deoxycytidine triphosphate is incorporated in the deoxycytidine sites of the DNA and the addition of another nucleoside to the gemcitabine DNA strand masks the incorporated gemcitabine from DNA repair [ 20 , 21 ]. In this way DNA chain elongation is inhibited and apoptosis is induced. Due to its mild toxicity profile gemcitabine is a suitable candidate for combination therapies and the combination of gemcitabine with DNA-damaging drugs such as alkylating agents, platinum complexes and radiotherapy appeared promising [ 20 , 21 ]. Gemcitabine was approved by the FDA in 1996 for the treatment of advanced pancreatic cancer [ 22 ]. Side effects of high-dose gemcitabine (1000 mg/m 2 ) include neutropenia, proteinuria, increased hepatic transaminase levels, nausea, vomiting, and mild skin rash [ 23 ]. Resistance factors of gemcitabine treatment include transporter deficiency (reduced hENT1 expression), overexpression of ribonucleotide reductases and of gemcitabine-deactivating cytidine deaminases [ 22 ]. In the latter case, 4-( N )-protection of gemcitabine with PEG, squalene or valproic acid as well as with linear carboxylic acids (valeroyl, heptanoyl, lauroyl, stearoyl) were successfully designed in order to overcome deamination [ 22 ]. The combination of gemcitabine with cisplatin was widely applied for the treatment of MPM before the combination of platinum complexes with anti-folates emerged as an improved first-line therapy option for MPM patients [ 24 ]. Currently, gemcitabine is casually applied as a second-line therapy of MPM [ 24 ]. A recent study of gemcitabine plus cisplatin/carboplatin in MPM patients underlined the efficacy and safety of this type of combination therapy for MPM patients [ 24 ]. In addition, gemcitabine plus the Vinca alkaloid vinorelbine was tested in a female MPM patient who was treated with pemetrexed before and because this patient showed partial response and tumor regression the gemcitabine plus vinorelbine combination therapy may represent a suitable salvage therapy for patients who are pre-treated with pemetrexed and suffer from a relapse [ 25 ]. Fig. 1 Structures of gemcitabine and ara-C (cytarabine). Fig. 1

Pemetrexed (Alimta ® ) is a folic acid analog comprising a pyrrolo[2,3-d]pyrimidine scaffold and acts as a folate antimetabolite against cancer ( Fig. 2 ) [ 26 ]. It is a potent inhibitor of pyrimidine and purine synthesis and inhibits vital enzymes such as glycinamide ribonucleotide formyltransferase (GARFT), aminoimidazolecarboxamide ribonucleotide formyltransferase (AICARFT) and thymidylate synthase (TS) [ [26] , [27] , [28] ]. Accumulation of toxic nucleotides as well as AMPK activation and mTOR inhibition contribute to the cytotoxic activity of pemetrexed [ 29 ]. Resistance mechanisms of pemetrexed include overexpression of TS, suppression of the folate transporter SLC19A1 (solute carrier family 19 member 1) and Akt activation [ 29 , 30 ]. Pemetrexed is clinically approved for the therapy of NSCLC and mesothelioma either as single agent or in combination with platinum complexes (cisplatin, carboplatin) [ 31 , 32 ]. It was superior to gemcitabine and showed promising results from various clinical studies with mesothelioma patients [ [33] , [34] , [35] ]. The combination of the anti-VEGF antibody bevacizumab with cisplatin plus pemetrexed showed improved results and the bevacizumab-cisplatin-pemetrexed therapy has become the standard therapy for MPM patients in France [ 36 ]. As already mentioned above, vinorelbine can be applied for mesothelioma patients pre-treated with pemetrexed [ 25 ]. Fig. 2 Structure of pemetrexed. Fig. 2

Gemcitabine, non-coding RNAs and mesothelioma

Several miRNAs were identified which regulate cancer cell sensitivity to gemcitabine treatment ( Fig. 3 ). Most of these gemcitabine-related results were obtained from pancreas and lung cancer samples, however, these identified miRNAs also play a crucial role for mesothelioma. Fig. 3 Gemcitabine, pemetrexed and non-coding RNAs in mesothelioma. Fig. 3

Let-7 miRNAs feature prominent examples of tumor suppressor microRNAs and let-7b, let-7c, and let-7d, for instance, were recently identified as tumor suppressors in mesothelioma [ [37] , [38] , [39] ]. Let-7d is overexpressed in MPM and may play a role concerning enhanced antimetabolite action [ 39 ]. Let-7c inhibited migration and invasion through ITGB3 and MAP4K3 targeting in NSCLC [ 40 ]. In pancreatic cancer, let-7 (let-7b/c/d) upregulation increased the activity of gemcitabine distinctly and, thus, it is conceivable that let-7 expression has beneficial effects on gemcitabine action in mesothelioma as well [ 41 ]. The tumor suppressor miR-16 was downregulated in samples from MPM patients who experienced extrapleural pneumonectomy [ 42 ]. Restoration of miR-16 expression by synthetic mimics suppressed anti-apoptotic Bcl-2 and showed in vivo anticancer activity in MPM xenografts [ 43 ] CCND1 featured another target of miR-16 and restored miR-16 also sensitized MPM cells to gemcitabine treatment [ 43 ].

The downregulation of tumor suppressing miR-34s turned non-malignant mesothelial cells into oncogenic cells [ 44 ]. In particular, miR-34a suppression was correlated with bad chemotherapeutic response of diffuse malignant peritoneal mesothelioma (DMPM), and c-MET and AXL were identified as targets of miR-34a in DMPM [ 45 ]. It was shown that miR-34a expression sensitized breast cancer cells to gemcitabine in a Linc-ROR-dependent way [ 46 , 47 ]. Tumorigenesis in MPM was correlated with suppression of the tumor suppressor miR-34b/c activity by methylation [ 48 ]. Vice versa, enhanced miR-34b/c expression induced antiproliferative effects, G1 phase cell cycle arrest and low motility of MPM cells [ 48 ]. In human osteosarcoma cells, increased miR-34b expression caused by treatment with the mTOR-inhibitor sirolimus led to increased gemcitabine activity [ 49 ].

The tumor suppressor miR-143 is distinctly suppressed in MPM patients as to analyses of resected and biopsy samples [ 50 ]. Recently, miR-143 increased the sensitivity of gemcitabine in bladder cancer cells via suppression of IGF-1R [ 51 ]. MiR-145 features another tumor suppressor, which is downregulated in MPM and exerts its activity by suppression of OCT4 and ZEB1 [ 52 ]. Indeed, the expression of miR-145 sensitized pancreatic adenocarcinoma cells to gemcitabine [ 53 ]. In contrast to that, the tumor suppressor miR-148a is highly expressed in mesothelioma and gemcitabine sensitizing effects of miR-148a were identified in pancreatic cancer models [ 54 , 55 ].

MiR-497 was suppressed in MPM cells and the miR-497 tumor suppressor enhanced gemcitabine activity in pancreatic cancer by downregulation of FGF2 and FGFR1 [ 56 , 57 ].

There are also oncogenic miRNAs commonly described as oncomirs that regulate gemcitabine activity aside the tumor suppressor miRNAs mentioned above. The expression of the oncomir miR-17-5p was high in short survivors of MPM [ 7 ]. Further to this, the suppression of miR-17-5p restored gemcitabine activity in pancreatic cancer cells by induction of Bim and, thus, miR-17-5p may play a role concerning gemcitabine activity against mesothelioma as well [ 58 ]. The oncomir miR-21 represents a well-documented oncogene in various cancers and so it was likewise overexpressed in MPM and suppressed PDCD4 (programmed cell death 4) in MPM [ 59 ]. MiR-21 expression led to gemcitabine resistance in breast and pancreatic cancer by upregulation of Akt signaling and suppression of PTEN [ 60 , 61 ]. Interestingly, treatment of pancreatic cancer cells with indole-3-carbinol (I3C) suppressed miR-21 expression via PDCD4 upregulation and overcame gemcitabine resistance in the end [ 62 ].

A list of miRNAs involved in gemcitabine resistance and sensitivity with connections to mesothelioma diseases is given in Table 1 . Table 1 MicroRNA tumor suppressors and oncomirs proven or strongly assumed to be correlated with gemcitabine activity in mesothelioma. Table 1 miRNA Target(s) Function Expression a let-7b Akt, Caspase 3, Twist, β-catenin tumor suppressor – let-7c ITGB3, MAP4K3 tumor suppressor lower in short survivors let-7d – tumor suppressor higher miR-15/16 Bcl-2, CCND1 tumor suppressor lower miR-17-5p Bim oncomir higher in short survivors miR-21 PDCD4, PTEN oncomir higher miR-30 FN1, vimentin, N-cadherin oncomir – miR-34a c-MET/Akt tumor suppressor lower miR-34b Bcl-2 tumor suppressor lower miR-143 IGF-1R tumor suppressor lower miR-145 OCT4 tumor suppressor lower miR-148a – tumor suppressor higher miR-497 FGF2, FGFR1 tumor suppressor lower a Expression in mesothelioma when compared with non-malignant/benign samples or other tumors.

Aside miRNAs, long-non-coding RNAs play a crucial role for the activity of gemcitabine in mesothelioma as well. Patients with high EF177379 (NEAT1) expression had prolonged overall survival times in case they haven't received induction chemotherapy [ 63 ]. NEAT1 expression sensitized cholangiocarcinoma to gemcitabine treatment in a BAP1-dependent way [ 64 ].

Aside NEAT1, there are further lncRNAs of importance for mesothelioma diseases. HOTAIR (HOX transcript antisense RNA) and MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) feature prominent examples [ 65 , 66 ]. Sarcomatoid mesothelioma was accompanied by shorter survival and revealed upregulated HOTAIR and MALAT1 expression [ 66 ]. Interestingly, it was shown that gemcitabine treatment induced HOTAIR expression in pancreatic cancer stem cells leading to drug resistance [ 67 ]. Similarly, MALAT1 expression led to gemcitabine resistance and enforced the stem cell character of cancer cells by induction of SOX-2 [ 68 ]. The suppression of PVT1 increased drug sensitivity in MPM cells [ 69 ]. Downregulation of anti-apoptotic BCL2L1, BCL2, ICEBERG (Caspase 1 inhibitor), and BIRC8 (Baculoviral IAP repeat-containing protein 8) as well as induced expression of pro-apoptotic LTB (lymphotoxin beta), BCL2L14 (Bcl-2 like protein 14), FASLG (FS ligand) and TNFRSF1B (tumor necrosis factor receptor superfamily member 1B) were the reasons for the enhanced chemosensitivity [ 69 ]. Suppression of EZH2 and PVT1 by curcumin restored gemcitabine activity in pancreatic cancer cells [ 70 ]. The role of the lncRNA Linc-ROR has already been mentioned above [ 46 ]. A list of long non-coding RNAs that may be involved in cisplatin resistance and sensitivity of mesothelioma is given in Table 2 . Table 2 Long non-coding RNA (lncRNA) tumor suppressors and oncogenes in mesothelioma proven or strongly assumed to be correlated with gemcitabine activity. Table 2 lncRNA Target(s) Function NEAT1 BAP1 tumor suppressor HOTAIR – oncogene MALAT1 SOX-2 oncogene PVT1 LTB, BLC2L14, FASLG, TNFRSF1B, BCL2L1, BCL2, ICEBERG, BIRC8, EZH2 oncogene Linc-ROR – oncogene

Pemetrexed, non-coding RNAs and mesothelioma

Pemetrexed owns a salient position in the therapy of mesothelioma and, thus, the identification of the influence of non-coding RNAs on pemetrexed activity is of great importance ( Fig. 3 ). Pemetrexed treatment induced let-7c expression in MPM which is of certain importance since let-7c was identified as a tumor suppressor in MPM [ 71 , 72 ]. In NSCLC, migration and invasion was suppressed by let-7c via regulation of its targets ITGB3 and MAP4K3 [ 73 ]. Similar to gemcitabine, restoration of tumor suppressor miR-15/16 and treatment of MPM cells with miR-16 mimic resulted in increased activity of pemetrexed [ 43 ]. In comparison with non-neoplastic pleura, the tumor suppressors miR-126 and miR-145 were suppressed in biopsies and resected MPM tumors [ 71 ]. Interestingly, MPM samples after pemetrexed plus cisplatin therapy exhibited reduced suppression profiles of miR-126 and miR-145 when compared with the untreated MPM samples which can be a reason for the relatively high efficacy of the cisplatin/pemetrexed combination therapy in MPM patients [ 71 ]. Indeed, upregulation of miR-145 enhanced the activity of pemetrexed against MPM cells [ 52 ]. Further to this, when compared with chemotherapy-naïve MPM biopsies the expression of the tumor suppressors miR-451 and miR-486-5p was significantly induced by pemetrexed/cisplatin combination therapy [ 71 ]. The expression of the tumor suppressor miR-34a was downregulated in diffuse malignant peritoneal mesothelioma (DMPM) [ 45 ]. It was shown that miR-34a also regulates a key factor of folate biosynthesis (methylene tetrahydrofolate reductase) and may function as a prognostic marker for the outcome of pemetrexed-based anticancer therapy [ 74 , 75 ]. MiR-203 features another tumor suppressor with relevance concerning MPM and it was downregulated in MPM [ 76 ]. In NSCLC samples from pemetrexed/cisplatin-treated patients a high miR-203 expression was correlated with drug sensitivity [ 77 ]. MiR-379, a regulator of IL-18, was also suppressed in pemetrexed-resistant MPM cells [ 78 ]. In addition, miR-202 was suppressed in asbestos-related lung cancer [ 79 ]. Interestingly, pemetrexed treatment of lymphoblastoid cells also downregulated miR-202 expression accompanied by upregulation of the miR-202 target MTHFD2 [ 80 ]. It is assumed that the formation of MPM is related to mesothelial hyperplasia. The expression of miR-494 was reduced in mesothelial hyperplasia and linked with FDZ4 expression [ 81 ]. In lymphoblastoid cells, induction of SUFU was linked with suppression of miR-494 in pemetrexed-treated cells [ 81 ]. In the same cells, pemetrexed also downregulated miR-1281 which is a miRNA upregulated in MPM patients and asbestos-exposed people [ 80 , 82 ].

As already mentioned above, the role of oncomirs such as miR-21 for the establishment of various cancer diseases is well described. MiR-21 was overexpressed in MPM and regulated mesothelin and PDCD4 [ 59 , [83] , [84] , [85] ]. Suppression of miR-21 might sensitize MPM to pemetrexed treatment and combination of pemetrexed with miR-21 antisense oligonucleotides in cationic solid lipid nanoparticles appears promising [ 86 ]. The oncomir miR-210 was also downregulated by pemetrexed plus cisplatin therapy when compared with therapy-naïve samples [ 71 ].

A list of miRNAs involved in pemetrexed resistance and sensitivity with connections to mesothelioma diseases is provided in Table 3 . Table 3 MicroRNA tumor suppressors and oncomirs in mesothelioma proven or assumed to be correlated with pemetrexed activity. Table 3 miRNA Target(s) Function Expression a let-7c ITGB3, MAP4K3 tumor suppressor lower in short survivors miR-15/16 Bcl-2, CCND1 tumor suppressor lower miR-21 PDCD4, PTEN, mesothelin oncomir higher miR-34a c-MET/Akt tumor suppressor lower miR-126 – tumor suppressor lower miR-145 OCT4 tumor suppressor lower miR-202 MTHFD2 tumor suppressor – miR-203 DKK1 tumor suppressor lower miR-210 NUPR1, HTRA1, RGS10 oncomir higher in short survivors miR-345 MRP1 tumor suppressor higher miR-379 IL-18 tumor suppressor lower miR-451 PSMB8, MIF, ERCC1 tumor suppressor lower miR-486 ARHGAP5 tumor suppressor lower in short survivors miR-494 FZD4, SUFU tumor suppressor lower miR-1281 – oncomir higher a Expression in mesothelioma when compared with non-malignant/benign samples or other tumors.

Concerning the effects of mesothelioma-correlated long non-coding RNAs on pemetrexed efficacy, a high expression of H19 was accompanied by poor response of NSCLC patients to pemetrexed-cisplatin combination therapy [ 87 ]. Similarly, MALAT1 expression was found to be inversely correlated with chemotherapy response including pemetrexed-based therapies [ 88 ].

Suitable non-coding RNA modulating drugs for the combination with gemcitabine or pemetrexed

The combination of gemcitabine or pemetrexed with other drugs, which can modify non-coding RNAs strongly associated with gemcitabine or pemetrexed efficacy in mesothelioma diseases, is of particular interest in order to achieve better therapy responses. Suitable combination drugs are either intended to suppress the expression of oncomirs associated with gemcitabine or pemetrexed resistance or to upregulate tumor suppressing non-coding RNAs in order to enhance the activity of gemcitabine and pemetrexed. It became clear that a good deal of possible combination drugs represent natural products or modified natural products. Prominent compound classes are featured by (poly-)phenols, terpenoids, alkaloids, fatty acids and HDAC inhibitors ( Fig. 4 ). Another example features the DNA-interacting drug cisplatin whose manifold non-coding RNA-modulating effects in mesothelioma were presented in a previous review [ 18 ]. In short, cisplatin treatment has casually led to the suppression of miR-21 and to the induction of let-7c, miR-34a, miR-145 and miR-451 [ 18 ]. Hence, cisplatin can possibly sensitize mesothelioma cells to treatments with gemcitabine or pemetrexed and it is widely applied as a first-line treatment for MPM patients in combination with pemetrexed [ 18 ]. Fig. 4 Non-coding RNA modulating drugs with relevance to gemcitabine or pemetrexed activity. Fig. 4

Phenolic compounds

It has recently been shown that (poly-)phenols can influence the response of various cancers by regulation of non-coding RNA expression. A prominent example is represented by the main catechin constituent of green tea plants ( Camellia sinensis ), epigallocatechin-3-gallate (EGCG), which is of interest for a wide audience because of the increasing popularity of green tea in the western world as a health-promoting life-style beverage [ 89 ]. Adverse effects of EGCG comprise certain liver toxic effects observed from some individuals taking high doses of EGCG or green tea extract as well as inactivating reactions with boronic acid drugs such as bortezomib [ 90 , 91 ].

Concerning a modulation of miRNAs with relevance to gemcitabine and/or pemetrexed activity, EGCG increased the expression of the tumor suppressors let-7b, let-7c, miR-15/16, miR-34a, miR-34b, miR-126 and miR-494 while the oncomirs miR-21, miR-30 and miR-210 were suppressed by EGCG in various cancer cells [ [92] , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] ]. Concerning lncRNAs, EGCG upregulated the expression of the tumor suppressor NEAT1 by induction of CTR1 in lung cancer cells [ 101 ].

Soy ( Glycine max ) is an integral component of the daily diet of millions of people all over the world and its isoflavone component genistein was identified as a suppressor of the oncomir miR-21. Further flavanoids such as glyceollins, 3,6-dihydroxyflavone (3,6-DHF), and silibinin suppressed miR-21 as well, while genistein, glyceollins, 3,6-DHF, and quercetin were able to induce the expression of the important tumor suppressor miR-34a [ [102] , [103] , [104] , [105] , [106] , [107] , [108] ]. In addition, miR-16 was upregulated by quercetin and miR-148a by glabridin [ [109] , [110] , [111] , [112] ]. The well-studied oncogenic lncRNA HOTAIR was distinctly suppressed by genistein [ 113 ].

Various bioactive components have been identified from popular Indian spices and one of the most prominent example, curcumin (diferuloylmethane), which is a natural polyphenol from the rhizome of the Indian spice turmeric ( Curcuma longa ), upregulated miR-15a, miR-16-1, miR-34a, miR-145, and miR-203, and suppressed oncogenic miR-17-5p and miR-21 [ [114] , [115] , [116] , [117] , [118] , [119] ]. Curcumin also regulated various lncRNAs. HOTAIR-dependent metastasis formation was blocked and the expression of oncogenic H19 and PVT1 was suppressed by curcumin [ 70 , 120 , 121 ]. In addition to curcumin, several new (semi-)synthetic curcuminoids such as CDF and EF24 have emerged as more potent anticancer compounds when compared with curcumin, and both CDF and EF24 downregulated miR-21 while CDF additionally suppressed miR-210 and induced miR-143 expression [ [122] , [123] , [124] , [125] ].

Various berries and grapes produce the anticancer active stilbene derivative resveratrol which was able to upregulate miR-34a while miR-21 was suppressed by resveratrol [ [126] , [127] , [128] , [129] , [130] ]. In addition, the expression of miR-143 was upregulated by the close resveratrol analog pterostilbene [ 130 ]. Concerning lncRNAs, resveratrol upregulated NEAT1 and suppressed MALAT1 [ 131 , 132 ]. Natural bisphenols such as honokiol exhibited distinct anticancer properties and honokiol upregulated miR-34a and miR-143 [ [133] , [134] , [135] ]. Emodin features a natural trihydroxy-anthraquinone with anticancer activity and emodin downregulated miR-210 while it upregulated miR-34a, miR-126 and miR-429 expression [ [136] , [137] , [138] , [139] ]. The polycyclic polyprenylated acylphloroglucinol (PPAP) garcinol features another interesting natural product, which was isolated from plums of the kokum tree ( Garcinia indica ), and downregulated miR-21 while the expression of tumor suppressing miR-494 was upregulated by garcinol [ 140 , 141 ]. Tumor suppressors were induced by other (poly-)phenols as well. MiR-148a was upregulated by caffeic acid, miR-15b by mangiferin (from mango) and miR-34a by pomegranate extract rich in polyphenolic components [ [142] , [143] , [144] ].

Last but not least, the approved phenolic anticancer drug etoposide, a topoisomerase II inhibitor derived from the natural product podophyllotoxin, displayed an induction of the tumor suppressor miR-34a in a p53-dependent way in cancer cells treated with etoposide [ [145] , [146] , [147] ]. Thus, a combination of gemcitabine or pemetrexed with etoposide appears promising for the treatment of mesothelioma diseases (see below).

A list of polyphenolic drugs and their effects on non-coding RNAs is given in Table 4 . Table 4 Polyphenolic drugs with effects on non-coding RNA tumor suppressors (inducing effects) and oncogenes (suppressing effects) including oncomirs and oncogenic lncRNAs in mesothelioma correlated with gemcitabine or pemetrexed activity. Table 4 Drugs Tumor suppressors Oncogenes EGCG let-7b, let-7c, miR-15/16, miR-34a, miR-34b, miR-126, miR-494, NEAT1 miR-21, miR-30, miR-210 Genistein miR-34a miR-21, HOTAIR Glyceollins miR-34a miR-21 3,6-DHF miR-34a miR-21 Quercetin miR-16, miR-34a – Silibinin – miR-21 Glabridin miR-148a – Curcumin miR-15a, miR-16-1, miR-34a, miR-145, miR-203 miR-17-5p, miR-21, HOTAIR, H19, PVT1 CDF miR-143 miR-21, miR-210 Resveratrol miR-34a, NEAT1 miR-21, MALAT1 Pterostilbene miR-143 – Emodin miR-34a, miR-126, miR-429 miR-210 Honokiol miR-34a, miR-143 – Garcinol miR-494 miR-21 Caffeic acid miR-148a – Mangiferin miR-15b Pomegranate extract miR-34a – Etoposide miR-34a –

Terpenoids

Terpenoids represent an important natural product class with distinct potential for the treatment of cancer diseases [ 148 ]. Paeoniflorin, a glucosylated monoterpene from Paeonia lactiflora , led to miR-16 upregulation in cancer cells [ 149 ]. The PEGylated monoterpene thymoquinone, a natural product isolated from Nigella sativa , induced the expression of the tumor suppressor miR-34a while the sesquiterpene lactone antrocin isolated from fungi upregulated let-7c expression [ 150 , 151 ]. Another sesquiterpene lactone, parthenolide from feverfew ( Tanacetum parthenium ) induced the expression of miR-15a and miR-16 [ 152 ].

The well-investigated diterpene retinoic acid (RA, vitamin A) caused expression upregulation of the tumor suppressors let-7c miR-15/16, and miR-223 [ 153 , 154 ]. In addition, 1,25-dihydroxyvitamin D 3 (1,25-D) upregulated miR-15a [ 155 ]. The vitamin E analog Δ-tocotrienol induced the expression of miR-34a [ 156 ]. Another vitamin E analog called antroquinonol upregulated miR-15/16 [ 157 ].

Triterpenes also feature a very interesting natural product class concerning potential anticancer drugs. Several triterpenes such as ursolic acid, cucurbitacin I, and ginsenoside Rh2 downregulated the expression of the oncomir miR-21, and Rh2 upregulated the tumor suppressor miR-148a [ [158] , [159] , [160] , [161] ]. AKBA (3-acetyl-11-keto-β-boswellic acid) represents another triterpene isolated from Boswellia plants and induced the expression of miR-34a [ 162 , 163 ].

The clinically approved terpenoid anticancer drug paclitaxel (taxol, ex Taxus brevifolia ) stabilizes microtubules and blocks mitosis in cancer cells [ 164 ]. As a single compound paclitaxel displayed no visible improvement against MPM in a phase II study when compared with standard therapy while curation of a peritoneal mesothelioma patient (a 71-years old woman) was observed in combination with carboplatin [ 165 , 166 ]. A more recent case study with nanoparticle albumin-bound paclitaxel in combination with carboplatin displayed repeated responses in an epitheloid MPM patient (a 76-years old man) [ 167 ]. Carboplatin/pemetrexed treatment did not work in this patient and, thus, albumin-bound paclitaxel plus carboplatin would be a suitable alternative for patients with cisplatin/pemetrexed-resistant MPM [ 167 ]. Interestingly, miR-34a expression was upregulated by paclitaxel treatment, which may play a role for combinations with other drugs [ 168 ]. Further to this, the paclitaxel analog docetaxel increased the expression of miR-34a in epithelial MPM cells [ 169 ].

A list of terpenoid drugs and their effects on non-coding RNAs is given in Table 5 . Table 5 Terpenoid drugs with effects on non-coding RNA tumor suppressors (inducing effects) and oncogenes (suppressing effects) in mesothelioma correlated with gemcitabine or pemetrexed activity. Table 5 Drugs Tumor suppressors Oncogenes Paeoniflorin miR-16 – PEG-Thymoquinone miR-34a – Antrocin let-7c – Parthenolide miR-15a, miR-16 – Retinoic acid let-7c, miR-15/16, miR-223 – 1,25-D miR-15a – Δ-Tocotrienol miR-34a – Antroquinonol miR-15/16 – Ursolic acid – miR-21 Rh2 miR-148a miR-21 AKBA miR-34a – Paclitaxel miR-34a –

Alkaloids

There are natural indoles of simple structure featured by 3,3‘-diindolylmethane (DIM) and indole-3-carbinol (I3C, from Brassica vegetables) which can regulate cancer-relevant miRNAs [ 170 ]. I3C was able to suppress miR-21 [ 62 , 171 ]. DIM, which is the condensation product of I3C built in the stomach, upregulated the tumor suppressors let-7b, let-7c, let-7d, and miR-34 [ [172] , [173] , [174] , [175] ].

Camptothecin derivatives (quinoline alkaloids from Camptotheca acuminata ) and Vinca alkaloids (indole alkaloids from Catharanthus roseus ) represent the most prominent examples of clinically approved anticancer alkaloids and the influence of miRNAs on their anticancer activity has been reviewed [ 176 ]. Camptothecin and its water-soluble derivatives irinotecan and topotecan represent quinoline alkaloid topoisomerase I inhibitors and the latter drugs are clinically approved against cancer [ 177 ]. Topotecan was able to induce miR-34b expression in cancer cells and might be a promising drug for combinations with gemcitabine [ 178 ].

Trabectedin (Ecteinascidin 743, Yondelis ® ) is a very promising tetrahydroisoquinoline isolated from the Caribbean tunicate Ecteinascidia turbinata showing a unique mode of DNA alkylation and this drug is currently clinically approved for soft tissue sarcoma treatment [ 179 ]. Meanwhile, results from clinical trials with epitheloid and sarcomatoid/biphasic MPM patients receiving trabectedin were published suggesting distinct activity of trabectedin against MPM [ 180 , 181 ]. Interestingly, trabectedin downregulated miR-21 expression in cancer cells and an influence by FUS-CHOP was proposed [ 182 ]. Hence, the combination of trabectedin with pemetrexed appears promising for the treatment of mesothelioma diseases. In addition, the oncogene miR-21 was suppressed by the isoquinoline alkaloid berberine (ex Berberis aristata ) [ 183 ]. Another natural isoquinoline called palmatine chloride induced the expression of miR-34a [ 183 , 184 ].

A list of alkaloid drugs and their effects on non-coding RNAs is given in Table 6 . Table 6 Alkaloid drugs with effects on non-coding RNA tumor suppressors (inducing effects) and oncogenes (suppressing effects) in mesothelioma correlated with gemcitabine or pemetrexed activity. Table 6 Drugs Tumor suppressors Oncogenes I3C – miR-21 DIM let-7b, let-7c, let-7d, miR-34 – Topotecan miR-34b – Trabectedin – miR-21 Berberine – miR-21 Palmatine miR-34a –

Miscellaneous natural products

Further natural products that don't belong to the compound classes mentioned above modulated miRNAs in cancers. Vitamin C (ascorbate), for instance, upregulated miR-345 expression [ 185 ]. Folic acid suppressed miR-21 expression [ 186 ]. Polyunsaturated fatty acids (PUFAs) induced the expression of let-7d and miR-15b [ 187 ]. In particular, docosahexaenoic acid (DHA), a vitamin F component (i.e., a polyunsaturated fatty acid/PUFA) from fish oil, was able to downregulate miR-21 while miR-126 expression was induced by DHA [ 188 , 189 ]. Diallyl disulfide (DADS), sulforaphane (SFN) and phenethylisothiocyanate (PEITC) feature natural organosulfur compounds commonly found in onions, garlic and leek. These organosulfurs upregulated various tumor suppressors such as let-7c (by PEITC), miR-34a (by DADS), miR-145 (by SFN), and miR-486 (SFN) [ [190] , [191] , [192] , [193] , [194] , [195] ].

A list of miscellaneous natural drugs and their effects on non-coding RNAs is given in Table 7 . Table 7 Miscellaneous natural drugs with effects on non-coding RNA tumor suppressors (inducing effects) and oncogenes (suppressing effects) in mesothelioma correlated with gemcitabine or pemetrexed activity. Table 7 Drugs Tumor suppressors Oncogenes Vitamin C miR-345 – Folic acid – miR-21 PUFAs let-7d, miR-15b, miR-126 miR-21 DADS miR-34a – SFN miR-145, miR-486 – PEITC let-7c –

HDAC inhibitors

Chromosomal DNA in eukaryotic nuclei is bound to highly alkaline histone protein octamers in order to form so-called nucleosomes which represent the main components of chromatin and play a crucial role for chromatin regulation [ 196 ]. Acetylation of lysine residues of histones reduces the positive charge and, thus, the lysine acetylation state of histone proteins controls gene expression. Histone acetylation as well as acetylation of other proteins (e.g., tubulin, p53) is regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs) [ 197 ]. There is only limited data available for HAT inhibitors concerning the regulation of non-coding RNAs. The natural HAT inhibitor garcinol and its effects on the regulation of non-coding RNAs are presented in Table 4 . The inhibition of HDAC enzymes has shown distinct anticancer effects and some HDAC inhibitors were already clinically approved for the treatment of T cell lymphoma and multiple myeloma [ 198 ]. In contrast to HAT inhibitors, manifold data concerning the influence of HDAC inhibitors on non-coding RNA expression is already available.

The sodium salt of butyric acid, sodium butyrate (NaB), was identified as an HDAC inhibitor of very simple structure. NaB induced the expression of the tumor suppressors miR-15/16, miR-126, miR-143, miR-145 and miR-202 [ [199] , [200] , [201] , [202] ].

The NaB derivative sodium phenylbutyrate (NaPBA) upregulated miR-34a and miR-148a [ 203 ]. The natural HDAC inhibitor trichostatin A (TSA) induced let-7b, let-7c, miR-15/16, miR-34a, miR-126, miR-202, miR-203, and miR-486 [ [204] , [205] , [206] , [207] ]. The synthetic HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat), which was approved for the treatment of T cell lymphoma, induced the expression of let-7d, miR-15a, miR-16, and miR-34b while the expression of the lncRNA HOTAIR was suppressed by SAHA [ [208] , [209] , [210] , [211] ]. In addition, SAHA suppressed miR-17-5p [ 212 ]. AR-42 upregulated let-7b, let-7d, miR-15b, and miR-34a while miR-17-5p and miR-21 were suppressed [ 213 ]. LAQ824 downregulated miR-21 [ 214 ]. Panobinostat (LBH-589) upregulated let-7b, miR-15a and miR-16 [ 208 , 215 ].

It has to be mentioned that HDAC inhibitors can casually also exert negative effects such as suppression of tumor suppressor miRNAs or induction of oncomirs. For instance, NaPBA downregulated miR-34b/c [ 216 ]. The approved drug SAHA led to suppression of miR-345 [ 210 , 217 ]. Panobinostat induced the expression of oncogenic miR-31 [ 218 ]. A detailed list of miRNAs regulated by HDAC inhibitors in various cancer entities was published [ 219 ]. Hence, caution is recommended and more research is necessary in order to find out if HDAC inhibitors represent suitable combination partners for gemcitabine or pemetrexed.

A list of HDAC inhibitors and their effects on non-coding RNAs is given in Table 8 . Table 8 HDAC inhibitors with effects on non-coding RNA tumor suppressors (inducing effects) and oncogenes (suppressing effects) in mesothelioma correlated with gemcitabine or pemetrexed activity. Table 8 Drugs Tumor suppressors Oncogenes NaB miR-15/16, miR-126, miR-202, miR-143, miR-145 – NaPBA miR-34a, miR-148a – TSA let-7b, let-7c, miR-15/16, miR-34a, miR-126, miR-202, miR-203, miR-486 – SAHA let-7d, miR-15a, miR-16, miR-34b HOTAIR AR-42 let-7b, let-7d, miR-15b, miR-34a miR-17-5p, miR-21 LAQ824 – miR-21 Panobinostat let-7b, miR-15a, miR-16 –

Pemetrexed as sensitizer for other approved anticancer drugs

Pemetrexed is currently applied as the first-line therapy for MPM patients. As mentioned above, the combination with other drugs can improve the activity of pemetrexed in a non-coding RNA mediated way. Vice versa, pemetrexed itself is a regulator of mesothelioma-relevant miRNAs such as the tumor suppressors let-7c, miR-451 and miR-486-5p as well as the oncomir miR-210 [ 71 , 72 ].

Doxorubicin (adriamycin) is a well-established anthraquinone topoisomerase II inhibiting anticancer drug [ 220 ]. One main resistance factor for doxorubicin treatment is represented by ABC-transporters which are associated with increased drug efflux and detoxification. The expression of the ABC-transporter MDR1 was regulated by miR-451 and re-expression of miR-451 sensitized breast cancer cells to doxorubicin [ 221 ]. Liposomised doxorubicin in combination with gemcitabine and carboplatin as third-line therapy exhibited distinct efficacy with a disease control rate of 60%, however, toxicity concerns arose and less toxic treatment options, maybe with pemetrexed instead of gemcitabine, are sought for [ 222 ]. Similarly, the water-soluble camptothecin derivative irinotecan, a clinically approved topoisomerase 1 inhibitor, was investigated for any relations with activity promoting miRNAs. Irinotecan in combination with cisplatin may have activity in mesothelioma patients [ 223 ]. Indeed, upregulation of miR-451 expression sensitized cancer stem cells to irinotecan treatment by suppression of the ABC-transporter ABCB1 which is responsible for the elimination of irinotecan in resistant cancer cells [ 224 ]. Hence, pemetrexed might increase the activity of doxorubicin and irinotecan in resistant cancer forms by induction of miR-451.

The Vinca alkaloid vinorelbine (navelbine) is often applied as a second-line therapy of MPM in case of relapse [ 225 ]. Vinorelbine exhibited moderate activity in pemetrexed-pretreated MPM patients [ 226 ]. Vinorelbine-resistant cancer cells revealed higher expression levels of miR-210 [ 227 ]. Since pemetrexed-based chemotherapy was able to suppress miR-210 expression a combination with vinorelbine appears promising.

Inhibitors of tyrosine kinases such as sunitinib and sorafenib were clinically approved for the treatment of various tumor diseases. In addition, sorafenib displayed considerable activity in a phase 2 trial for pemetrexed/platinum-pretreated malignant mesothelioma [ 228 ]. Sorafenib-resistant cancer cells showed low expression levels of the tumor suppressors let-7c and miR-34a [ 229 ]. As already mentioned above, pemetrexed-based chemotherapy upregulated let-7c and miR-34a and features a suitable combination option for sorafenib ( Fig. 5 ). Fig. 5 Possible activity boost of approved anticancer drugs by pemetrexed-mediated miRNA modulation. Fig. 5

Conclusions

Non-coding RNAs can modulate gemcitabine and pemetrexed activity in mesothelioma in various ways that either sensitize or harden cancer cells to antimetabolite treatment. In addition, gemcitabine and pemetrexed actively modified the expression profiles of non-coding RNAs in mesothelioma. It is possible to use the already known facts about the interactions between non-coding RNAs and gemcitabine or pemetrexed in order to identify both problems and chances. Facing these facts, future research efforts should provide more details about the relationship between non-coding RNAs and gemcitabine or pemetrexed treatment in order to improve the therapy of mesothelioma diseases with high mortality rates and to prolong the survival times of mesothelioma patients as well as their quality of life.

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