Non-Curcuminoids from Turmeric and Their Potential in Cancer Therapy and Anticancer Drug Delivery Formulations

Cancer is a fatal disease, which accounts for high mortality and low survival rate worldwide. The International Agency for Research on Cancer (IARC) has estimated that, by 2030, about 21.7 million recently-developed cancer cases and about 13 million cancer-related deaths would result because of the heterogeneous nature of cancerous cells and failure of most of the chemotherapeutic agents in achieving the desired objective [ 1 , 2 ]. Therefore, the universally perturbed issue of obtaining economical therapeutic efficiency and reduced side effects are creating a fervent interest among researchers on traditional medicines such as black pepper, garlic, ginger, turmeric etc. [ 3 , 4 ]. Continuous studies on the epidemiological patterns of these naturally occurring plant-derived medicines especially turmeric elucidate their imperative role in reducing the mortality by cancer [ 5 , 6 , 7 ]. Turmeric ( Curcuma longa L.), a nutritional dietary spice from the Zingiberaceae family, has been extensively used for various applications. This rhizomatous herbaceous perennial plant found abundantly in Asia is renowned for its cosmetic, culinary, color, and medicinal applications for centuries [ 7 , 8 ]. Basically, its volatile oil and nonvolatile oleoresin constitutes of bioactive components, which are classified as diphenylheptanoids (nonvolatile) diphenylpentanoids (nonvolatile), phenyl propene (cinnamic acid type) derivatives (nonvolatile), turmeric oil containing terpenoids (volatile) [ 9 ]. Major diphenylheptanoids are curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which are collectively called curcuminoids [ 10 , 11 ]. Non-curcuminoids can be defined as all the biologically active compounds other than curcuminoids, precisely, curcumin-free bioactive components of turmeric [ 12 ]. Curcuminoids have a mixed bag of biological activities such as anti-inflammatory, antiulcer, antiviral, antibacterial, antiprotozoal, antivenom and antioxidant. In addition, anticoagulant, antihypotensive, antihypocholesteremic, antifibrotic, antimutagenic, antifertility, and anticancer activities, which are well documented. Especially, the anticancer activities of curcuminoids are well established and evidenced with extensive studies on vivid disparate pathways to trigger apoptosis and cell cycle arrest are well established [ 13 , 14 , 15 ]. Recently, non-curcuminoids such as turmerones, elemene, bisacurone, curdione, cyclocurcumin, germacrone, furanodiene, curcumol, and calebin A were extensively studied, for their pharmacological activities such as anti-inflammatory, antioxidant, and anticancer activities. Researchers have specifically explained that non-curcuminoids have a broad spectrum of anticancer activities on different cell lines including intricate and drug resistant malignancies. Although these compounds promise to exhibit similar potency as curcuminoids, their anticancer studies are elusive and they still have to become a cynosure [ 12 , 16 ]. In this review, we comprehensively attempt to establish the basic attributes including the identification, composition, physicochemical properties, and various anticancer activities, including the mechanism of action and molecular docking studies of non-curcuminoids having equipotent synergistic effects as curcuminoids. Its therapeutic efficacy is also evinced by evaluating the successful clinical trials. Furthermore, we reviewed distinctive approaches that tend to ameliorate the solubility and bioavailability to aggrandize the anticancer effects of non-curcuminoids.

Turmeric has a diverse chemical composition, principally containing approximately 235 terpenoids and phenolic compounds [ 12 ], which are obtained through various extraction procedures. To be specific, there are about 6–8 monomeric phenylpropenes, 22 diarylheptanoids and diarylpentanoids, 109 sesquiterpenes, 68 monoterpenes, four steroids, two alkaloids, five diterpenes, three triterpenoids, fatty acids, and 12 other compounds, along with sugar, proteins, carbohydrates, fiber, minerals, and resin that were isolated and identified [ 12 , 32 ]. One important class among them are diarylhepatanoids that include curcuminoids, are polyphenolic compounds containing curcumin (diferuloyl methane) and its two derivatives demethoxycurcumin, bisdemethoxycurcumin. Their distinct compositions were found to be in the ratio, namely curcumin (70–80%), demethoxycurcumin (18–20%) and bisdemethoxycurcumin (2–10%) [ 12 ], these diarylhepatanoids also include some curcumin-free compounds, such as tetrahydrocurcumin and cyclocurcumin. Other non-curcuminoids involve 109 sesquiterpenes [ 33 ], which are primarily found in turmeric oil, such as three elemanes, namely α-elemene, β-elemene, and γ-elemene; 54 bisabolanes, mainly α-turmerone, β-turmerone, ar-turmerone, bisacurone, and curlone; six germacranes, mainly germacrone, dehydrocurdione, β-germacene, and germacrone-13-al; along with seven guaianes, four selinanes, two caryophyllanes, aristolene, carbane, cedrane, bergamotane, and himachalane. From these sesquiterpenes, bisabolanes were found in the greatest abundance. In addition, few phenylpropenes, such as calebin A and ferulic acid, and some monoterpenoids, such as carvacrol and limonene, were also reported [ 12 ]. Hence, the enumerate curcumin-free compounds exhibiting distinctiveness in their composition, as well as biological activities, comprises turmerone, turmeronol, turmerine, himachalane, bergamotane, aristolene, silinanes, carbrane, cedrane, dihydrozingerone, sesquisabinane, sesquiphellandrene, curcumene, elemene, bisacurone, curdione, cyclocurcumin, germacrone, furanodiene, curcumol, calebin A, acrone, santalane, guaiane, curlone, carvacrol, limonene, tetrahydrocurcumin, hexahydrocurcumin, octahydrocurcumin, and ferulic acid [ 12 ].

Elemenes, (1-methyl-1-vinyl-2, 4-diisopropenyl-cyclohexane) are among the 109 sesquiterpenes present in turmeric [ 32 ]. The potency of elemene, isolated from turmeric, has been already stated in China’s food and drug administration and is extensively used in the chemotherapy of the cancer patients in China. Many investigations have led to the fact that elemene can inhibit the tumor growth of various cells, such as ovarian, laryngeal, non-small cell lung, prostrate, melanoma, leukemia, breast, brain, hepatoma, colorectal adenocarcinoma, glioblastoma, and human cervix epithelioid carcinoma cells due to its apoptotic behavior [ 45 ]. Hua et al. demonstrated the antitumor activity of elemene by studying the inhibition property of it on HL-60 cell proliferation. This behavior is associated with cell cycle arrest between phase transitions from S to G2M phase, thereby promoting apoptosis [ 46 ]. Elemene can also pass through the blood brain barrier combating the carcinomas of the brain due to its small size and lipophilic nature [ 47 ]. Elemene is found in three different structural isomers, namely α, β, and γ-elemene; among them, β-elemene is abundantly found and is more active than the other components. 4.2.1. β-Elemene β-elemene, (1S,2S,4R)-1-ethenyl-1-methyl-2-4-bis(prop-1-en-2yl) cyclohexane, is a sesquiterpene which is studied for its anticancer activity in various cancer cells through its antiproliferative activity with subsequent induction of apoptosis. The research catalog of β-elemene has a range of studies dealing with their effects on different cancer cell lines, mainly on non-small cell lung cancer (NSCLC) cells and the effective mode of action to trigger apoptosis. To begin with, a study explained the effect of β-elemene on these cells caused cell death through the mitochondrial release of the cytochrome c-mediated apoptotic pathway. These lung cancer cells were arrested at the G2-M phase, which caused a decrease in levels of phosphor- cell division cycle (cdc)2 (Thr-161) and cyclin B1, with an increase in the levels of phosphor-cdc2 (Tyr-15) p27kip1 and partially by the check point kinase (CHK)2-dependent mechanism [ 48 ]. Li et al. reported that β-elemene sensitizes human NSCLC lines (Aa549 and H460), to cisplatin. This was due to the mitochondria-mediated intrinsic apoptosis pathway which involves IAPs (inhibitor of apoptosis proteins) and Bcl-2 family proteins in a time and dose-dependent manner. Hence β-elemene and cisplatin combination proved to be a promising regimen for the treatment of lung cancer and cisplatin-resistant tumors [ 49 ] ( Figure 3 B). Further, investigation of β-elemene on human non-small cell lung cancer A549 cells by Shu et al. explained that β-elemene inhibited the activity of the P13K/Akt/ mammalian target of rampamycin (mTor)/ribosomal protein S6 kinase beta-1(p70S6K1) signaling pathway, resulting in protective autophagy and apoptosis [ 50 ]. Li et al. also reported the rapid inhibition of ERK and Akt activation and upregulation of Casitas B–lineage lymphoma (c-Cb1 and Cb1-b) expression, which enhanced apoptosis in a dose-dependent manner in lung cancer cells (A549) [ 51 ]. Furthermore, the intensive antiproliferative effect of β-elemene on NSCLC cells was proved by AMP-activated protein kinase (AMPKa) and ERK1/2 mediated inhibition of transcription factor Sp1, followed by reduction in DNA (cytosine-5)-methyltransferase 1 (DNMT1) protein expression. This study also found that metformin intensifies the effect of β-elemene by blocking Akt signaling and inhibits DNMTI protein expression. In addition, the reciprocal of AMPKa and ERK1/2 signaling pathways are responsible for β-elemene responses [ 52 ]. It was also noticed that β-elemene, isolated from C. aromatica and combined with etoposide, proved very beneficial for lung cancer [ 53 ]. β-elemene has a promising therapeutic role in human SGC7901 and MKN45 gastric cancer cells. β-elemene inhibited the cell viability and clonogenic survival of gastric cancer cell that were decreased in a dose-dependent manner, with induction of apoptosis [ 54 ]. The effects of β-elemene in murine hepatocellular cancer, and the relation with its expression level of c-Met (a receptor tyrosine kinase) were examined over neoplastic tissues. Analysis through western blot, immunofluorescence analysis and reverse transcription polymerase chain reaction (RT-PCR) confirmed the presence of c-Met expression in H22 hepatocellular carcinoma xenograft model in vitro and in vivo. The test results showed that the induction of growth inhibition in murine hepatocellular carcinoma cells by β-elemene was brought about by downregulation of c-Met expression [ 55 ]. It was further found by Zhan et al. that β-elemene inhibits human renal carcinoma (RCC) 786-0 cell proliferation by inhibition of PI3K/Akt/mTOR and mitogen activated protein kinase (MAPK)/ERK signaling pathways, thus inducing protective autophagy and apoptosis [ 56 ]. Another study explored the efficacy

Furanodiene, (5E,9E)-3,6,10-trimethyl-4,7,8,11-tetrahydrocyclodeca[b]furan, another sesquiterpene extracted from the volatile oil fraction of turmeric by CO 2 supercritical fluid technique. Fuanodiene had inhibitory effect on various cells, such as HL-60 (promyelocytic leukemia), HeLa (cervical carcinoma), SGC—7901 (gastric cancer) HeLa, K562 (leukemia), A549 (lung adenocarcinoma), MDA-MB-435s (breast cancer) HT-1080 (fleshy tumor), Hep-2 (laryngocarcinoma), SMMC-7721(hepatoma), and PC3 (prostatic carcinoma), displaying their benevolent potential with varied mechanisms of action. In hepatoma cells (Hep G2), the potency of furanodiene was demonstrated by DNA fragmentation assay. The inhibition of cell proliferation brought cell cycle arrest at the G2/M phase and apoptosis through the mitochondria-caspase apoptotic pathway, which activated p38, and inhibited the ERK/MAPK signaling pathway [ 74 ]. Another study evaluated the effects of furanodiene on human leukemia cell HL60 by DNA fragmentation and indicated that furanodiene brought apoptosis through cleavage of caspase 3, caspase 8, caspase 9, and PARP. Along with this, the Bcl-2 family proteins and BID protein were activated, whereas Bax, Bcl-xl, and Bcl-2 proteins were not at all affected by the stimulation of furanodiene. It was also seen that furanodiene promoted upregulation of tumor necrosis factor receptor 1 (TNFR1), with the formation of TNFR1 complex along with the production of TNF-α in HL60 cells [ 75 ]. Ba et al. studied the anticancer activity of furanodiene on HeLa, HL-60, U251, and Hep-2 cells. and explained that furanodiene is effective against uterine cervix cancer (U14) cells and has a protective effect on immune function [ 76 ]. Further, the effect of furanodiene, studied on HeLa cells, revealed that furanodiene in a dose-dependent manner caused cell death. This proved its efficacy on sarcoma 180 cells in mice and uterine cervical cancer growth [ 77 ]. Further, successful development and validation of the pharmacokinetic parameters of furanodiene in rat plasma through tandem mass spectrometry and liquid chromatography were studied. The results explained that the bioavailability of furanodiene in rats was about 49%, which proved that their method of analysis might be helpful to prove the potency of furanodiene as an anticancer agent [ 78 ]. Another study showed that furanodiene inhibited protein expression of total cyclin D1, p-cyclin D1, p- cyclin-dependent kinases inhibitors (CDK)2, total CDK2, pRb, total Rb, Bcl-Xl, and Akt. These expressions suppressed breast cancer cell growth both in vitro and in vivo and increased the protein expressions of Bax and Bad, along with elevation of proteolytic cleavage of caspase 9, as well as caspase 7 and PARP [ 79 ]. Furanodiene has also proved its efficacy in the inhibition of human umbilical vascular endothelial cells and proliferation carried out by VEGF [ 80 ]. There were many studies, which reflected the usefulness of furanodiene in combinational therapy to combat various cancer cells. Xu et al. studied the antiproliferation activity of furanodiene on lung cancer cells A549, NIH-H1299, and 95-D and studied its usefulness in combination therapy with paclitaxel. This study observed the inhibition of colony formation in 95-D cells and A549 cells and that it facilitated upregulation of protein expression levels of binding immunoglobulin (BIP), mRNA and C/EBP homologous protein (CHOP), as well as its accumulation in the nucleus, inducing endoplasmic reticulum (ER) stress. Further, they studied that furanodiene efficiently causes cell metastasis in 95-D lung cancer cell, by activating the signaling molecules and regulating G1 cell cycle arrest, thereafter inducing apoptosis and autophagy. This autophagy was involved in the enhancement of the expression of light chain3-II (LC3-II) in the protein level. Due to this, downregulation of the protein levels of full PARP surviving, Bcl-2 and pro-caspase 7 and upregulation of cleaved PARP, affected the signaling molecules that promote apoptosis. It was also seen that furanodiene inhibited cell proliferation in a concentration-dependent manner as well as caused blockage of cell cycle progression in G1phase by downregulating the protein levels of cyclin D1 and CDK6 and upregulating those of p27 and p21 in 95-D cells [ 81 ]. Zhong et al. also studied the combined effects of tamoxifen (TAM) and furanodiene in human breast cancer cell in vitro. This research showed that the enhancement of growth inhibitory and pro-apoptosis behavior of furanodiene, enhanced the pro-apoptosis and growth inhibitory activity of tamoxifen. This activity induced cell cycle arrest via mitochondrial-caspase dependent, PARPg-independent and CDKs-cyclin signaling pathway in human breast cancer cells without affecting the cytotoxicity of Tamoxifen [ 82 ]. Furanodiene, when treated on breast cancer cell lines MCF-7 and MDA-MB-231 suppressed proliferation and increased the lactate dehydrogenase

Curcumol, (1S,2S,5S,9S)-9-isopropyl-2-methyl-6-methylene-11-oxatricyclo (6.2.1.01,5) undecan-8-ol, is a potent anticancer sesquiterpenoid that inhibits proliferation of Hela, OV-UL-2, MCF-7, and MM231 cancer cells by RNA synthesis in a concentration-dependent manner. It caused cell death in ARTE- induced human lung adenocarcinoma (ASTC-a-1) with the induction of cell cycle arrest at G2/M phase with nuclear fragmentation, phosphatidylserine externalization, and rapid Bax translocation from the cytosol into mitochondria [ 89 ]. Huang et al. revealed that curcumol brought apoptosis in nasopharyngeal carcinoma CNE-2 cells by downregulation of NF-κB. This compound also showed promising anticancer effects in ASTC-a-1 cell by apoptosis mechanism, mediated by caspase-independent mitochondrial pathways [ 90 ]. Curcumol when treated on hepatic stellate cells (HSC) induced apoptosis by suppression of PI3K, Akt and Ikappa B. This suppression was due to the decrease in NF-κB and its DNA binding activity leading to the decrease in Bcl-2, Bcl-xl, and increase in Bax expression along with the increase in caspase 3 [ 91 ] ( Figure 3 e). In addition, the anticancer effects on colorectal cancer LOVO cells were enhanced by curcumol. This study showed that when curcumol was treated on these cells decreased Bcl-2 and increased Bax to induce apoptosis. Further, the suppression of insulin-like factor-1 receptor (IGF-1R) escalated the phosphorylation of p38 MAPK and decreased Camp-response element (CREB) expression to trigger apoptosis [ 92 ]. Thus, these studies elucidated the anticancer activities of curcumol on different types of cancers through different mechanism of action that ultimately led to cell cycle arrest and apoptosis that hold a promising path to acknowledge them as effective anticancer agents.

Calebin A(CA),(3E)-4-(4-hydroxy-3-methoxyphenyl)-2-oxobut-3-en-1-yl(2E)-3-(4 hydroxy-3-methoxyphenyl) prop-2-enoate), isolated from C. longa , has a ferulic acid ester bond which lacks the 1, 3-diketonic structure of curcuminoid compounds. Many researchers have shown that calebin A is beneficial in combating numerous cancerous cells such as colon, gastric, multiple myeloma, breast cells as well as multi-resistant cancer cells. A study of calebin A suggested that it is an effective compound in chemotherapy for multi-drug resistant cancers, as it inhibits the growth of the cell and induced apoptosis in SGC7901/Vincristine cells, a multi-resistant (MDR) human gastric adenocarcinoma cell line, A549/DDP (cisplatin)-MDR pulmonary carcinoma cell line and HepG2/ADM (Adriamycin)-MDR hepatoma cell line. This study revealed that drug efflux function of p-glycoprotein was inhibited with their treatment, but the expression level of P-glycoprotein remained the same. Calebin A was also found to modulate the activities of MAPK, which included increased protein kinase of p38, 38kda activity. They also, decreased JNK as well as ERK. These results suggested that this is a genuine compound for the treatment of human gastric and other MDR cancers [ 96 ]. Calebin A was found to be very effective for HCT-116 type colon cancer cells and has proved to be more potent, when compared with curcumin. The expression of regulatory protein of cell cycle such as cyclin-A, cyclin-B, cdc25A, cdc2 levels are decreased by calebin A, causing S and G2/M cycle arrest and increases the CDKI p53 and p21. In fact, this compound increases the ROS levels, which again leads to cell cycle arrest as it promotes the DNA damage response and upregulate the phosphorylation of H2A histone family member X on serine 139 to form (γH2AX ), CHK1, and CHK2. When intraperitoneally administrated on colon tumor cell in vivo, they showed decreases in the tumor volumes, tumor sizes and the cell nuclear antigen (PCNA) protein levels [ 97 ] ( Figure 3 F). Tyagi et al. identified calebin A from C. longa , utilized mouse macrophages and electrophoretic mobility shift assay in vitro. This study showed that CA causes suppression of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation of macrophages and forms osteoclasts, with downregulation of marker gene expression of RANKL-induced osteoclastogenesis, including calcitonin receptor (CTR), tartrate-resistant acid phosphatase (TRAP), nuclear factor of activated T-cells cytoplasmic (NFATc–1), and cathepsin K. Additionally, suppression of phosphorylation, followed by the degradation of kB, NF-κB, which were the main source for the suppression of osteoclastogenesis that induced multiple myeloma and breast cancer [ 98 ]. Taken together, calebin A, alike curcumin exerts anticancer activities mainly on colon cancer cells through induction of apoptosis and cell cycle arrest. These compounds have positive results on breast cancer cells and even on multi-resistant cancers.

Bisacurone, (6S)-6- [(1R, 4S, 5S)-4, 5-dihydroxy-4-methylcyclohex-2-en-1-yl]-2-methylhept-2-en-4-one, is a terpenoid, known as a very potent anticancer agent. Studies showed that vascular cell adhesion molecules-1 (VCAM-1) promoted carcinogenesis. Therefore, Sun et al. carried out investigation to find an herbal remedy for its suppression and found that Bisacurone in TNF-α activated by human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner inhibits the level of VCAM-1. It showed significant blockage of the NF-κB p65 carried to the nucleus, phosphorylation of inhibitory factor kBα and suppression of ROS. Bisacurone, also showed inhibition of phosphorylation of protein kinase C (PKC) and Akt that helps in the regulation of VCAM-1 by TNF-α. Thus, they prove to be potential anticancer agent by their promising results in regulating VCAM-1 [ 106 ] ( Figure 3 h).

There are many studies, which prove the efficiency of non-curcuminoids. A recent study demonstrated that the total extract of turmeric is more superior to curcuminoids alone. This fact was assessed by methylthiazolyldiphenyl tetrazolium bromide (MTT assay), which concluded that the cell viability or proliferation decreased in cancer cells especially lung cancer cells. Additionally, isobolographic assessment revealed that when total extract of turmeric when used synergistically with cisplatin, the dose of cisplatin used can be reduced than the actual dose to bring similar effect with less toxicity and adverse effect as treatment with cisplatin alone [ 111 ]. Many evidence-based studies have also been initiated since long, which emphasize the therapeutic potential of the components of turmeric. Numerous clinical trials have been conducted for curcumin, which denote the clinical potential of them having a safe uptake of 12 g/day. These clinical studies also claim that curcumin is very efficient in treating various forms of cancer such as colorectal, breast, head, and neck, pancreatic, and so on [ 112 ]. Even clinical trials on the safety and therapeutic efficacy of curcumin-free compounds have been reported, some of which are still ongoing [ 113 ]. Among them, β-elemene, a green drug extracted from C. longa , which is still extensively studied and also accredited by the Ministry of Health People’s Republic of China and State Pharmacy of China to be the most beneficial compound for medical purposes, mainly against numerous forms of cancer including non-small cell lung cancer cell (NSCLC), liver, brain, esophageal squamous cell carcinoma, and so on [ 114 ]. In earlier trials, the safety and efficacy of β-elemene used in combination was validated through controlled, randomized clinical trials. These trials involved around 1467 patients divided into group of two for studying NSCLC and small cell lung cancer (SCLC). Accelerated improvement in the survival and tumor response rate were observed with minimal side effects in patients treated with β-elemene injection as adjunctive for lung cancer in contrast to patient given medication without β-elemene injection [ 115 ]. Joshi et al. also validated that turmeric oil is safe as per the phase I trials on nine healthy volunteers and efficient as a chemopreventive agent especially in submucous fibrosis [ 116 ]. Another successful investigation was carried on 102 patients with esophageal squamous cell carcinoma who underwent chemoradiotherapy and, thereafter, were subjected to surgery. The recurrence rate with usual chemotherapy regimen for esophageal squamous cell carcinoma was about 60%, decreasing the survival rate. Therefore, this clinical trial with β-elemene treatment increased the survival (overall and progression free) rate and decreased the toxicity level related to synchronous chemoradiotherapy with cisplatin and 5-fluorouracil regimen [ 114 ]. Certain ongoing clinical trials are facing efficacy problems due to lack of promised delivery at specific tissue sites, these can be rectified if non-curcuminoids are encapsulated in different vesicles to facilitate target delivery. The combination of turmeric oleoresin (mainly ar-turmerone and 1,8 cineole) with β-cyclodextrin through co-precipitation or kneading method can form inclusion complexes, improved the solubility of turmeric oleoresin, which was determined through phase solubility studies. These complexes can improve the biological activities of non-curcuminoids significantly [ 117 ]. In this way, there are numerous studies, which improve the authentic properties of non-curcuminoids specially the solubility, bioavailability as well as stability and focus on such formulations can be a breakthrough in the clinical trials. Our research team, Aurea Biolabs, took initiative and formulated a novel technique, PNS technology, involving a complete natural turmeric matrix comprising of turmeric water extract, turmeric essential oils, and curcuminoids. In addition, a series of clinical trials were conducted to prove the potency of this matrix to deliver efficiently the most bioavailable form of curcumin to the target site. An open labeled parallel arm comparative study with two other curcumin formulation was conducted. This study engaged 45 healthy male candidates who were given a single dose of 500 mg through oral administration. This comparative study proved the worth of this formulation in contrast to the other two formulations in improving the solubility and bioavailability enormously. To ascertain the claimed high bioavailability of this formulation, a pilot crossover study was undertaken on 12 healthy male adults and the blood samples for curcumin content were analyzed. The results were promising as 10 times more increase in bioavailability was witnessed than curcumin (95% purity) as measured by concentration maximum (C max ) and area under the curve (AUC) values [ 118 ]. With the continuous success of these studies, a

Liposomes are spherical bi-layered vesicles having phosphate head of phospholipids, which are hydrophilic and fatty acid tails (lipids), which are hydrophobic. There were many liposomal non-curcuminoids formulations studied recently with β-elemene and furanodiene. Chen et al. explained various formulations including liposomes of β-elemene and zedoary turmeric oil. Their formulation helped prolong the circulation of turmeric oil liposomes, reduce the irritation and improved the efficacy of β-elemene by encapsulating them in PVP-coated liposomes. Moreover, in vivo studies revealed that liposomal β-elemene were distributed in spleen, kidney, and liver in rats after intravenous administration. Another study summarized the recent advances in the liposomal delivery system of β-elemene exhibiting anticancer activity, mainly on lung cancer because of the various benefits such as availability, angiogenesis inhibition, induction of apoptosis, and enhancement of radiosensitivity. It also exhibited chemotherapeutic effects when combined with other anticancer agents and exhibited minimal side effects, such as damage of kidney and liver function. System biology, network pharmacology and clinical trials provided adequate evidence of β-elemene as a potent anti-lung cancer agent. This also proved that the advancement in molecular pharmaceutical technologies provided a broad platform for making it suitable for liposomal-based delivery [ 122 ]. Furanodiene hold diverse pharmacological activities ranging from high lipophilicity to poor stability. Comparative research by loading furanodiene with biodegradable polylactide-co-glycolide (PLGA) and pegylated PLGA nanoparticles showed improvement in the stability, hydrophilicity and bioavailability of furanodiene, thus facilitating the permeation of furanodiene across Caco-2 cell monolayers [ 123 ]. Furthermore, FN-loaded FA-PEG2000-DSPE-modified nanostructured lipid carriers (FA-FN-NLCs) were developed by using emulsification-ultrasonic and low temperature solidification method, optimized with central composition design, to increase the solubility and bioavailability of FN. The advantages being, increased circulation time in blood and improved targeting ability. Hence, this formulation emerged as an optimistic drug delivery system for FN in the treatment of cancer exhibiting high encapsulation efficiency and loading capacity. Even, through NiR fluorescence imaging study, it was seen that FA-FN-NLCs especially accumulated in tumor site, by receptor-mediated endocytosis. In vitro drug release exhibited a biphasic release pattern with an initial sudden drug release and followed by a prolonged drug release. In vivo study compared with FN solution (FN-SOL) and FN loaded traditional NLCs (FN-NLCs) and showed that FA-FN-NLCs had a longer blood circulating time (t 1/2 ) and higher AUC [ 124 ]. Recently, Pan et al. compared calebin A and calebin A encapsulated liposomes and concluded that liposomes of calebin A increased the bioactivity of calebin A by enhancing its anticancer activity in colon cancer. This study explained that, besides enhanced solubility, liposomal calebin A has the potency to change absorption pathway and signaling processes in an increased manner, establishing it as a promising agent in inhibiting colon cancer (SW480) cells [ 125 ]. Therefore, these studies explain the significant increase in the anticancer activities of non-curcuminoids through liposomal formulation.

Nanocapsules are nanoscale shell made from non-toxic polymeric membrane, which encapsulates an inner liquid core. Natrajan et al. developed chitosan-alginate nanocarrier for the encapsulation of ar-turmerone, which resulted in a clear supernatant and through hemolysis assay, confirmed that they were hemocompatible. The carrier showed high cell viability percentage, which insinuate it as nontoxic and with nanoscale shell. Moreover, turmeric oil loaded nanocapsules were found to have antiproliferative activity on A549 cell lines by using MTT assay [ 126 ]. Hence, this suggests that non-curcuminoid loaded nanocapsules may also accelerate their anticancer activities.

Microemulsions are clear and thermodynamically stable; they are formed by isotropic liquid mixtures of oil, water and surfactant, where oil phase contains different olefins and hydrocarbons whereas aqueous phase contains salt or other constituents. Ju et al. proved that elemene microemulsions are beneficial for the treatment of malignant neoplasms, such as gynecological, breast, skin, lung, and gastrointestinal cancers and, hence, exhibit sustained release in vivo with improved bioavailability, stability, high entrapment efficiency and good clarity. In addition, it was found that submicron emulsion possessed high turmeric oil loading capacity. This can stay stable and sterilized at room temperature, as well as under high temperature, pressure for six months [ 122 ]. Gao et al. through in vivo studies suggested that β-elemene nanoemulsion inhibited the evolution of hepatoma 3B cells more efficiently in contrast to β-elemene water solution in a concentration-dependent manner [ 127 ]. Thus, micro and nano emulsions improve non-curcuminoids bioavailability and solubility to ameliorate their anticancer activities.

Non-curcuminoids are basically all other biologically active compounds of turmeric excluding curcuminoids. The latter has been well established in the research field for promoting green drug discovery. However, this review attempts to resolute the foundation for non-curcuminoids by highlighting a literature-based summary on their dynamic anticancer potential. The discovery, chemical composition including the structure and physicochemical properties of these bioactive compounds provide a useful scaffold of knowledge about each component. In addition, certain non-curcuminoids have shown similarity in their chemical structures as curcuminoids for example cyclocurcumin and calebin A. Some major non-curcuminoids such as bisacurone, elemene, turmerones, furanodiene, germacrone, curcumol, calebin A and curdione are considered in this review, which help apprehend that, the anticancer activities of these compounds that can be comparable to curcuminoids. Indeed, the alteration in various signaling pathways such as NF-ĸB, TNF and inhibition of enzymes such as COX-2, protein kinase, cytokines and MMPs transcription factors as well as blocking cancer cell proliferation at different phases of cell cycle such as G1, G2, M, S to induce apoptosis, are comparable to the cancer fighting mechanism of curcuminoids. Further, modulation of p-glycoprotein in non-curcuminoids could increase the uptake by the cells; help them to act synergistically with curcumin. Moreover, the molecular docking studies of elemene, germacrone, cyclocurcumin have been discussed which gives a thorough knowledge of the most favorable binding sites of these compounds, which reveal that these compounds hold a promising place as an anticancer agent to fight against various cancers. These similarities in structure and mechanism of action prove that non-curcuminoids are equipotent and highly effective as curcuminoids and can be used in combination or alone with the latter. Additionally, both are extracted from turmeric with certain variation in the end process and hence, these compounds provide an added perquisite to be established in the medicinal world. Moreover, various preclinical and clinical studies of these compounds were conducted to have an extensive understanding to recondite the mechanism of action and anticancer activities on in vivo rat and human models. However, these compounds possess certain physicochemical issues particularly issues pertaining to its low solubility and bioavailability, therefore, attempts to revamp the anticancer activities by numerous encapsulation techniques help conceal the debits of these curcumin-free compounds. Proper selection of delivery systems for non-curcuminoids are promising, especially with PNS technology, which has successfully identified these compounds, along with curcumin components without any distortion of shape or size. In fact, this technology is a feather in the cap of these versatile non-curcuminoids, which prove promising benefits when used in combination with a more bioavailable form of curcumin. Clinical studies were also conducted on these formulations based non-curcuminoids which consolidate promising results that make them strong contender in the medicinal market to fight numerous diseases especially cancer. However, more studies on the exclusive therapeutic benefits of these components through more clinical trials on varied catalogs such as by considering larger group of cancer patients, extending treatment regimen duration and monitoring safe effective dose can promulgate its universal acceptance. This review tries to unveil the promising effects of non-curcuminoids by giving an insight on researches conducted up until now. Nevertheless, more studies including the bioavailability, drug interactions, effect on multi drug resistance and chemopreventive activities when used alone or in combination with other cancer treatment drug can provide them as an epitome of economical cure and relief in the discipline of medicine. These benefits acknowledge a wide scope for various cancers, late or early stage cancers and recurrent cancers, which would help in the decline of relapses and death rate. To summarize, this review is an integrative approach to promote these natural compounds as an affluent and benevolent source for future studies.