# Sesquiterpene Lactones and Cancer: New Insight into Antitumor and Anti-inflammatory Effects of Parthenolide-Derived Dimethylaminomicheliolide and Micheliolide

Authors: Yubo Dong; Xuanjin Qian; Jian Li
Journal: Computational and Mathematical Methods in Medicine
 (2022)

---

## Abstract

Applied science nowadays works on the isolation and application of biological macromolecules (BMM). These BMM are isolates from plants using different techniques and used as anticancer, antimicrobial, and anti-inflammatory drugs. Parthenolide (PLT) is one of the most important biological macromolecules and a naturally occurring sesquiterpene lactone that is isolated from a plant speciesTanacetum parthenium (T. parthenium). The anti-cancer and anti-inflammatory effects of PTL isolated from T. parthenium were previously reported and summarized in detail. These biological activities make it a vital candidate for further researches and drugs development. As per the previously obtained findings, the sesquiterpene is very much known for some biological activities; therefore, the anti-cancer and anti-inflammatory activities of the sesquiterpene were critically reviewed. During the research process, PTL was found to be unstable in both acidic and basic conditions with low solubility, so structurally related compounds micheliolide (MCL) and Dimethylaminomicheliolide (DMAMCL) (a prodrug of MCL) were developed. In this article, we briefly review the therapeutic effects of PTL and its derivative DMAPT on inflammatory diseases and tumors, focusing on the current application of PTL in targeted therapy and combination therapy, together with anti-inflammatory and anti-tumor functions of MCL and DMAMCL. The uniqueness of this biological macromolecule is not to harm the normal cell but target the cancerous cells. Therefore, the current literature review might be helpful and useful for prospects based on the effects of MCL and DMAMCL on cancer.


---

## Body

## 1. Introduction

Medicinal plants have long been prized for their medicinal benefits. Plants produce a wide range of compounds as both constitutive and secondary metabolites. Aromatic chemicals, usually phenolic compounds, or their oxygen-substituted derivatives, are found in traditional therapeutic plant extracts [1]. Sesquiterpene lactones are plant metabolites that have long been used to treat high fevers, headaches, stomachaches, toothaches, rheumatoid arthritis (RA), menstrual abnormalities, and other inflammatory illnesses in traditional medicine [2]. Parthenolide (PTL) is an important sesquiterpene lactone observed in medicinal plants, especially in feverfew (Tanacetum parthenium). The methylene of PTL, lactone ring and epoxide group, are nucleophilic, allowing for quick interactions with biological locations [3].Sesquiterpene lactones (SLs) are mostly from the Asteraceae family with the effect of anti-inflammatory and other biological activities, including antitumor, cytotoxic, and antibacterial, since 1970. PTL, MCL, and DMAMCL are the members of sesquiterpene lactone family, with the effect of anti-inflammatory and anti-tumor. Nevetheless, PTL is unsteady in acidic and basic conditions. While Micheliolide (MCL) is more stable than PTL; its half-time is 2.64 hours. But studies show that its activity is significantly reduced in vitro. Dimethylaminomicheliolide (DMAMCL) has a long half-time. Pharmacokinetics suggest that DMAMCL has high bioavailability when taken orally. DMAMCL can be slowly and continuously converted to MCL for up to 8 hours, and it can maintain the effective concentration of MCL in plasma and passes through the blood-brain barrier. Guaianolide sesquiterpene lactones, a source to discover agents that selectively inhibit acute myelogenous leukemia (AML) stem and progenitor cells. Previously, abundant studies have been conducted regarding the anti-inflammatory and anti-cancer biological molecules. Therefore, the current study was aimed at collecting online data and compiling it in the form of review literature which could be helpful and opening novel research directions for scientists.


## 2. Parthenolide (PTL): A Germacrane Sesquiterpene Lactone Exhibiting Potent Anti-Inflammatory and Anticancer Properties

PTL, with known potent anti-cancer and anti-inflammatory properties, is a SL originally isolated from the plant Tanacetum parthenium, PTL plays anti-inflammatory effect through an underlying mechanism, and the mechanism attenuates the production of inflammatory mediators possibly via inhibiting the Toll-like receptor 4-mediated activation of Akt, mTOR, and NF-κB pathways to attenuate the production of inflammatory mediators [4]. Thus, PTL has the potential to be a promising therapeutic agent to treat different inflammation-related disorders, such as migraine headaches, RA, and colon inflammation [5]. Notably, PTL is probably one of the herbal candidates for clinical assessment because it is useful in reducing the mortality of patients with severe COVID-19 [6]. The therapy effect may be attributed to the reduction of cytokine IL-6 induced by PTL [6, 7]. PTL is the first small molecule found to be against cancer stem cells (CSC) [8]. Also, it has recently been manifested that PTL may induce apoptotic in various human cancer cells as a potential agent, including colorectal cancer (CRC), chronic myeloid leukemia (CML), pancreatic cancer, osteosarcoma cancer, and breast cancer [9–14]. PTL could not only induce apoptotic but also exert antiproliferative effect on cancer cells. For instance, PTL may inhibit lung cancer growth by suppressing IGF-1R-mediated PI3K/Akt/FoxO3α signaling and inhibit the development of non-small-cell lung cancer cells thorough B-Raf/MAPK/Erk pathway [15]. Moreover, ubiquitin-specific peptidase 7 (USP7) plays a critical part in cancer development. Besides, PTL could suppress colorectal cancer cell growth by inhibiting USP7/Wnt signaling [16]. Finally, several studies have reported that PTL have an effect on cell migration/invasion and the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells through inhibition of transforming growth factor β1 (TGF-β1) and NF-κB [17, 18]. Although PTL has shown potent antitumor potential in various cancer cells, its high lipophilicity and low solubility limit the oral bioavailability and solubility of the drug in blood plasma [8]. To circumvent this limitation, the water-soluble Michael adducts of PTL and dimethylaminoparthenolide (DMAPT) were developed, and it has shown enhanced bioavailability and solubility in comparison with PTL. It was found that DMAPT could increase reactive oxygen species (ROS) levels and inhibit NF-κB activation [10]. In a recent study, NF-κB inhibition by DMAPT was demonstrated to radiosensitize NSCLC via blocking DNA double-strand break (DSB) repair [19]. Furthermore, DMAPT was also regarded as a potential agent for breast cancer, bladder cancer, and lung cancer [20–22].Despite of frequent production of antitumor effects from PTL and DMAPT, the agents do not demonstrate biological activity corresponding to the dose administrated because they cannot discriminate effectively between normal and cancerous cells. To cultivate pharmacological efficacy of PTL, serial tumor-targeted preparations such as nanocarriers and liposomes have been developed. Improved efficacy and minimized side-effects of lung cancer treatment was proved due to the combined administration of PTL and ginsenoside CK in liposomes with targeted tLyp-1 ligand through specific delivery to the target sites and induction of lung cancer apoptosis [23]. Combined use of natural products in nanocarriers was also able to be considered as attractive therapeutic methods. PLGA-antiCD44-PTL nanoparticles improved the drug delivery and bioavailability by selectively targeting leukemic cells [24]. Some disadvantages have been cited by the previously published data. For instance, in a study, there are some disadvantages such as poor bioavailability and low water solubility [25]. Another disadvantage is that these biological extracts are obtained from the plants. But plants are seasonal, and it is very hard to find the proper and unique plants to obtain these biological molecules. The PTL has been found to be an inhibitor of Nuclear Factor Kappa B (NF-κB) [26]. Therefore, the inhibition of the NF-κB pathway by PLT could enhance lung cancer and decrease transcription factors and pulmonary arterial hypertension [27].


## 3. MCL, Synthesized from PTL, Exert Its Anti-Inflammatory and Anticancer Effects through Modes of Crosstalk between NF-κB and Other Signaling Molecules

Although PTL has anti-inflammatory and anti-tumor functions, it was found unstable in both acidic and basic conditions [28]. Thus, the structurally related compound MCL was developed. As a natural guaianolide sesquiterpene lactone, MCL, was found in Michelia compressa and Michelia champaca plants and could also be synthesized from PTL in vitro. As has been shown, MCL exhibit potent anti-inflammatory properties and broad-spectrum anti-cancer activity comparable to that of PTL, but is more stable than PTL in both vitro and vivo [29]. And its specific structure, α-methylene-γ-lactone, might be responsible fore its underlying mechanism. The exomethylene group enables MCL to alkylate p65 cysteine-38 and inhibit DNA binding to p65/NF-κB subunit, exerting a NF-κB antagonist effect [8]. The NF-κB family of transcription factors was found 30 years ago and has turned into a crucial player in inflammation and innate immunity by cooperating with multiple other signaling molecules or pathways and eventually releasing important anti-inflammatory factors. Due to the important inflammatory effect of NF-κB, it plays a key part in inflammatory-related diseases, e.g., RA, inflammatory bowel disease, and autoimmunity. Also, diseases composed of a critical inflammatory component such as cancer and atherosclerosis were included [30]. Hence, it was concluded that the MCL has the potential to exert its anti-cancer and anti-inflammatory effects through the inhibition of NF-κB.A direct contribution of the NF-κB signaling pathway is suggested by studies with transgenic mice to the development of a variety of inflammation-linked disorders. In a dextran sodium sulphate- (DSS-) induced murine model of colitis, DSS significantly increased the expression level of IL-1β, TNF-α, and IL-6 which have prominent effects on the pathogenesis of IBD and treatment with MCL significantly reduced DSS-induced release of these pro-inflammatory cytokines via regulating the NF-κB signaling pathway [31]. The pro-inflammatory cytokines mentioned above also have a crucial role in the pathophysiology of RA [32]. Therapeutic effects of MCL on RA were shown through a murine model as well. The potential mechanisms of its therapeutic function may also include alterations in the expression of cytokines C5/C5a, TIMP-1, M-CSF, and BLC [33].A different inflammation-associated type of disease is Sepsis. Lipopolysaccharide (LPS) can bind to Toll-like receptor 4 (TLR4) to produce large amounts of inflammatory cytokines and exerts a decisive effect in the occurrence of sepsis [34]. Apart from reducing the activation of NF-κB as mentioned above, MCL can also reduce various inflammatory cytokines mediated by LPS by inhibiting the phosphorylation of p70S6K (Thr389) and Akt (Ser473) [35]. Besides, a recent study has demonstrated that MCL also provides a therapeutic role in sepsis caused by G+ bacteria and antibiotic-resistant bacteria in a similar way [36]. Later, when studying the regulatory effect of MCL on the immunopathology of tuberculosis caused by Mycobacterium tuberculosis (Mtb), the mechanism of MCL treatment of inflammation-linked disorders was verified again. MCL reduces the secretion of inflammatory cytokines (TNF-α and IL-1β) induced by Mtb in a dose-dependent manner. Moreover, MCL inhibits Mtb-induced Akt (Ser473) phosphorylation in Raw264.7 and then lowers down the activation of NLRP3 inflammasome [37]. As a neuroprotective agent, MCL may also inhibit neuroinflammation in neurodegenerative disorders [38]. In respect of the above mechanism, it was concluded that MCL could be viewed as an effective agent against a series of inflammation-related diseases where the NF-κB signaling pathway plays a key part in, including IBD, colitis, RA, sepsis, and tuberculosis.NF-κB pathway, the most prominent factor involved in the inflammation-fibrosis-cancer axis, plays a critical part not only in inflammatory diseases but also in diseases composed of a vital inflammatory component, e.g., cancer [39]. Mechanisms for the transition from inflammation to cancers may be related to several regulatory molecules covering chemokines, proinflammatory cytokines, TNF, and IL-6 which exert an essential effect in the growth, proliferation, and invasion of cancer cells [40]. It is well known that colitis-associated cancer (CAC) can result from chronic colonic inflammation, so MCL could have the potentially be a therapeutic agent for patients with CAC [31]. Firstly, IKKβ-induced NF-κB within enterocytes functions significantly in tumor initiation during the early stages. Secondly, IKK2-mediated NF-κB activity within myeloid cells subserves tumor progression through stimulating the expression of proinflammatory cytokines that may act as tumor growth factors [41]. Therefore, MCL could be used as an NF-κB inhibitor to treat CAC.Another type of cancer associated with inflammation is hepatocellular carcinoma (HCC) which is driven by the inflammatory cytokines TNF-α and IL-6 and their downstream targets NF-κB, JNK, and STAT3 [42]. Firstly, NF-κB within hepatocytes appears to be required by tumors linked to chronic inflammation to act as an antiapoptotic survival factor. Through protecting tumor cells from death or enhancing their proliferation, the activated IKK/NF-κB pathway may exert a tumor-promoting effect [39]. Secondly, activated NF-κB family members drive IL-6 expression, and IL-6 can phosphorylate and activate STAT3 [43]. There are two pathways in the process of STAT3 activation, and one of them is transsignaling which can induce the production of proinflammatory cytokines which drives chronic inflammation [44]. Phosphorylated STAT3 can enter the nucleus and induce cell proliferation and metastasis [45, 46]. Compared with Stat3f/f mice, there was more than a 6-fold reduction in HCC multiplicity and significantly smaller tumors discoverd in hepatocyte-specific STAT3-deficient mice (Stat3Δhep). And the above indicated that STAT3 was needed for the growth and survival of HCC cells [47]. Thirdly, the NF-κB pathway can modulate CSC features during hepatocarcinogenesis, and CSC is of great importance in the initiation and progression of HCC [39]. Using the xenograft liver cancer model formed by injecting Huh7 cells into nude mice, it is also found that MCL suppresses liver cancer cells by triggering apoptosis and perturbing actin cytoskeleton. Hence, MCL is able to expected as a potent therapeutic agent for liver cancer [48].Being a malignant tumor, gastric carcinoma originates from the epithelium of the gastric mucosa. What’s worse, it comes first in the incidence of various malignant tumors in my country. Patients suffered from gastric cancer are inclined to a younger population, owing to alterations in diet, growing work pressure, and Helicobacter pylori infection. Currently, combination of neoadjuvant chemoradiotherapy, molecular-targeted therapy, and immunotherapy is the principal treatment for advanced gastric cancer [49]. However, the prognosis keeps poor in patients with advanced gastric cancer [50]. Consequently, it is necessary to improve the prognosis of patients who suffer from advanced gastric cancer. In a recent study, upregulation of IL-6 is noticed in gastric cancer tissue, predicting that gastric cancer patients have a poor prognosis. The above situation may be related to IL-6’s ability to promote tumor cell invasion, metastasis, and angiogenesis [46]. Additionally, the significance of IL-6 was manifested by a study concerning gastric tumorigenesis in mice induced by N-methyl-N-nitrosourea in promoting gastric cancer cell proliferation via STAT3 stimulation by comparing IL-6 knockout mice with wild-type (WT) mice [51]. Therefore, blockade of the IL-6/STAT3 pathway may be an effective treatment for gastric cancer. The effects of MCL on gastric cancer were found that MCL suppresses the growth of gastric cancer via blocking IL-6/STAT3 pathway [52]. Hence, it was concluded that the MCL could have the ability to treat patients with gastric cancer and may ameliorate the prognosis of patients who have advanced gastric cancer.


## 4. DMAMCL: An Anti-Inflammatory and Anticancer Prodrug Derived from MCL

Dimethyl amino MCL is the dimethyl amino Michael adduct of MCL, showing higher stability, increased activity, and lower toxicity than MCL. When orally administrated with a much longer half-life than DMAPT, DMAMCL possesses strong anti-inflammatory effects [31]. We have mentioned the function of MCL in the treatment of inflammatory bowel diseases and other inflammatory diseases. In addition to the various inflammatory diseases mentioned above, DMAMCL has also been shown to act as a therapeutic agent in diabetic kidney disease (DKD) and neuroinflammation, which was like the effect of MCL. It is observed that DMAMCL induce metadherin (Mtdh) downregulation which inhibits NF-κB signaling activation and suppresses its downstream inflammatory cytokines. For this reason, DMAMCL could inhibit Mtdh-mediated renal inflammation in DKD [53]. In addition, DMAMCL was reported to alleviate NLRP3-mediated neuroinflammation and may inhibit the progression of Parkinson’s disease (PD) by attenuating the NLRP3 inflammasome [54].DMAMCL produces MCL as a metabolite at a slow but continuous speed in plasma. Thus, better pharmacokinetic properties and the potential to become a promising anti-tumor agent are shown on DMAMC. Besides, DMAMCL triggers apoptosis in HCC cells and cell cycle arrest at the G2/M phase, and inactivating the PI3K/Akt pathway by accumulating ROS [55]. Therefore, DMAMCL is a promising agent for the treatment of HCC.Glioblastoma (GBM) is regarded as the most malignant and most aggressive form of primary malignant brain tumor. Standard treatment for GBM involves surgical resection combined with followed radiotherapy and chemotherapy using temozolomide (TMZ), which has a very poor patient prognosis. Thus, new therapeutic drugs or combination therapies need to be developed urgently to overcome the serious obstacles of tumor heterogeneity, CNS penetration, and drug resistance [56]. Currently, for the treatment of GBM, DMAMCL is in phase I clinical trials (trial ID: ACTRN12616000228482) and has been designated as an orphan drug for GBM by the FDA. Many articles have introduced and supplemented the treatment mechanism of MCL on glioma. It was demonstrated that PAI-1 was the direct target of DMAMCL, and ACT001 directly binds PAI-1 to inhibit the PAI-1/PI3K/AKT pathway. Inhibition of the PAI-1/PI3K/AKT pathway inhibits glioma cell proliferation, invasion, and migration. Furthermore, DMAMCL inhibited STAT3 phosphorylation by directly binding to STAT3 [57]. Phosphorylated STAT3 binds to programmed death receptor 1 (PD-L1) promoter and modulates PD-L1 transcription in glioma cells [58]. Thus, inhibition of STAT3 results in decreased PD-L1 expression [57]. Moreover, MCL, released from DMAMCL, could selectively bind to monomeric PKM2 and promote its tetramerization. Activated PKM2 rewires the aerobic glycolysis and suppresses proliferation of GBM cells [59]. In addition, DMAMCL may target the Bcl-2 signal pathway to attack glioma cells [60]. Finally, DMAMCL induce apoptosis and autophagy by regulating the ROS/mitogen-activated protein kinase (MAPK) and the Akt/mTOR signaling pathways in the U87-MG and U251 cell lines [61].DMAMCL could decrease the percentage of AML stem cells in primary AML cells [62]. As mentioned above, MCL binds to PKM2 and stimulates the irreversible tetramerization of PKM2, which can suppress the proliferation of GBM cells. Currently, it is also determined that DMAMCL markedly inhibits the leukemia cells growth as a PKM2-targeted therapeutic agent [63]. Rhabdomyosarcoma (RMS) and osteosarcoma are the most common soft tissue sarcoma and primary malignancy of bone, respectively. They both occur in teenagers and children in most cases, which have recently been effectively treated by DMAMCL. The underlying mechanism may be due to Bim induction, NF-κB pathway, ROS generation in RMS cell lines, and reduction in stemness of osteosarcoma stem cells caused by DMAMCL [64, 65]. Based on abovementioned obtained findings, it was concluded that DMAMCL could be an eco-friendly alternative compound for treating cancer cells because DMAMCL is the dimethyl amino less toxic than some other chemical anticancer compounds.


## 5. Advantages of Dimethylaminomicheliolide (DMAMCL)

Based on the above studies, the DMAMCL has been elaborated very clearly and compared with some other natural drugs. The published findings have concluded that the DMAMCL have many advantages over MCL and PLT. The DMAMCL has been found a suppressor for the proliferation of GBM cells through targeting pyruvate kinase 2 and help in rewiring aerobic glycolysis [59]. Peritoneal fibrosis (PF) is principally responsible for ultrafiltration failure in patients experiencing long-term peritoneal dialysis and effective treatments. However, DMAMCL has been found a new compound with an advantage of low toxicity, high stability, and sustainable release of MCL [66]. Another research revealed that the LC50 values of DMAMCL against C6 and U-87MG cell lines in vitro were 27.18±1.89 μM and 20.58±1.61 μM, separately. Apart from that, the DMAMCL have remarkably lowered down the anti-apoptosis gene Bcl-2 and elevated apoptosis in C6 and U-87MG cells in a dose-dependent manner. Moreover, this study concluded that the DMAMCL possessed great potential for the treatment of glioma [60]. In respect of the above significant findings, it was concluded that the DMAMCL is a pharmaceutical product that has profound applications against different types of disease and infections and has several advantages.


## 6. Discussion

### 6.1. Combination Therapy for Various Cancers Involving PTL, MCL, and DMAMCL

Combination therapy may have a better therapeutic effect than monotherapy, inhibiting tumor growth and improving survival ratio. Moreover, long-term high-dose monotherapy often leads to serious side effects and drug resistance. Thus, two or more drugs are often used in combination to enhance the curative effect, reduce adverse drug reactions, and treat different symptoms or comorbidities. In recent years, PTL, MCL, and DMAMCL have shown significant potential to participate in combination therapy and have been reported to be applied to the treatment of various diseases and improve the existing treatment methods.The mechanism and therapeutic effect of PTL used to treat various diseases have been comprehensively studied. In recent years, the synergistic benefits of PTL combined with other drugs have been gradually discovered compared to monotherapy. In human AML cells, the combination of PTL and pan-histone deacetylase inhibitors (HDACIs) potentiates HDACI lethality by blocking NF-κB and subsequent MKK7-dependent activation of the SAPK/JNK pathway [67]. Several years later, it was determined that treatment with PTL results in upregulation of NADPH via pentose phosphate pathways (PPP) and activation of the Nrf2-mediated responses. In order to overcome these obstacles, a triple-drug regimen named PDT comprising 2-deoxyglucose, PTL and temsirolimus was designed and has shown potent therapeutic effects on primary AML cells. It is worth mentioning that this PDT regimen is also effective for AML specimens that are resistant to PTL alone [68]. In treating human colorectal cancer and colitis-associated colon cancers (CAC), balsalazide, a prodrug of 5-aminosalicylate, has the potential to chemoprevent colorectal cancer in patients with ulcerative colitis [69]. Coadministration of balsalazide with PTL synergistically inhibits activation of NF-κB, potentiating the efficacy of balsalazide [70]. In the MDA-MB-468 breast cancer cell line, Epirubicin shows apoptosis as well as anti-cancer effects, but it is also cytotoxic to normal cells. The combination therapy of PTL and Epirubicin showed the same antiproliferation and proapoptosis effects. Still, due to the lack of cytotoxicity of PTL on normal cells, the drug side effects were reduced [71]. Triple-negative breast cancer has the worst prognosis of treatment and the highest risk of distant metastasis among all types of breast cancer. New strategies are required to enhance tumor sensitivity to agents and enhance the therapeutic effect. Carlisi et al. demonstrated that combined treatment of SAHA and PTL synergistically sensitized MDA-MB231 breast cancer cells to the cytotoxic effect of PTL [72]. In another study, PTL was proved to prevent resistance of triple-negative breast cancer cells to doxorubicin and mitoxantrone by suppressing the overexpression of Nrf2 [73]. In addition, the application prospects of combination therapy in treating advanced HCC have also been recently discovered. The PTL nanocrystal delivery system was used in combination with sorafenib (Sora) to treat tumors in mice with HCC. The tumor inhibition rate reached 81.86%, far exceeding that of individual PTL and Sora, which means that the combination drug not only improves the poor water solubility of PTL but also enhances the therapeutic effect [74]. Next, it was reported that PTL also strengthened the drug sensitivity of gastric cancer cells to DDP and reverse the drug resistance of human gastric cancer cells via suppressing the STAT3 signaling pathway [75]. TMZ, the most applied chemotherapeutic drug to treat GBM after operation [76]. Inhibition of NF-κB leads to in anti-glioma activity and lowers TMZ-induced chemoresistance through down-regulating MGMT gene expression [77].DMAMCL, MCL, or PTL may not fully eradicate GBM. Thus, combination treatment of ACT001 with other therapies has also developed in recent years [57]. ACT001 and cisplatin act synergistically to suppress the PAI-1/PI3K/AKT pathway, increasing the apoptosis of glioma cells and overcoming cisplatin resistance in glioma cells [78]. DMAMCL can diffuse through the blood-brain barrier (BBB) and build up in the brain [79], resulting in decreased PD-L1 expression, while its side effects are required to be solved urgently. Thus, DMAMCL would probably be regarded as the best option in combination with TMZ for GBM treatment to reverse the immunosuppression and inhibit GBM cell immune escape caused by TMZ [80].Nowadays, L-3,4-Dihydroxyphenylalanine (L-DOPA) is applied in the treatment of Parkinson’s disease (PD) as the main agent but may cause serious side effects if used continuously. DMAMCL and low dose of L-DOPA were proved to be equivalent to the administration of L-DOPA in a high dose in PD in mice, suggesting that DMAMCL enhance the curative effect of L-DOPA on PD [81]. Combination treatment of MCL and radiotherapy can ameliorate the sensitivity of cancer tissues to radiotherapy and enhance the therapeutic effect of radiotherapy. MCL effectively cultivates radiosensitivities of p53-deficient non-small-cell lung cancer by inhibiting the HIF-1α pathway via promoting HIF-1α degradation [82]. MCL-mediated depletion of GSH reduces the occurrence of KLF4-mediated cisplatin resistance in breast cancer cells [83].


## 6.1. Combination Therapy for Various Cancers Involving PTL, MCL, and DMAMCL

Combination therapy may have a better therapeutic effect than monotherapy, inhibiting tumor growth and improving survival ratio. Moreover, long-term high-dose monotherapy often leads to serious side effects and drug resistance. Thus, two or more drugs are often used in combination to enhance the curative effect, reduce adverse drug reactions, and treat different symptoms or comorbidities. In recent years, PTL, MCL, and DMAMCL have shown significant potential to participate in combination therapy and have been reported to be applied to the treatment of various diseases and improve the existing treatment methods.The mechanism and therapeutic effect of PTL used to treat various diseases have been comprehensively studied. In recent years, the synergistic benefits of PTL combined with other drugs have been gradually discovered compared to monotherapy. In human AML cells, the combination of PTL and pan-histone deacetylase inhibitors (HDACIs) potentiates HDACI lethality by blocking NF-κB and subsequent MKK7-dependent activation of the SAPK/JNK pathway [67]. Several years later, it was determined that treatment with PTL results in upregulation of NADPH via pentose phosphate pathways (PPP) and activation of the Nrf2-mediated responses. In order to overcome these obstacles, a triple-drug regimen named PDT comprising 2-deoxyglucose, PTL and temsirolimus was designed and has shown potent therapeutic effects on primary AML cells. It is worth mentioning that this PDT regimen is also effective for AML specimens that are resistant to PTL alone [68]. In treating human colorectal cancer and colitis-associated colon cancers (CAC), balsalazide, a prodrug of 5-aminosalicylate, has the potential to chemoprevent colorectal cancer in patients with ulcerative colitis [69]. Coadministration of balsalazide with PTL synergistically inhibits activation of NF-κB, potentiating the efficacy of balsalazide [70]. In the MDA-MB-468 breast cancer cell line, Epirubicin shows apoptosis as well as anti-cancer effects, but it is also cytotoxic to normal cells. The combination therapy of PTL and Epirubicin showed the same antiproliferation and proapoptosis effects. Still, due to the lack of cytotoxicity of PTL on normal cells, the drug side effects were reduced [71]. Triple-negative breast cancer has the worst prognosis of treatment and the highest risk of distant metastasis among all types of breast cancer. New strategies are required to enhance tumor sensitivity to agents and enhance the therapeutic effect. Carlisi et al. demonstrated that combined treatment of SAHA and PTL synergistically sensitized MDA-MB231 breast cancer cells to the cytotoxic effect of PTL [72]. In another study, PTL was proved to prevent resistance of triple-negative breast cancer cells to doxorubicin and mitoxantrone by suppressing the overexpression of Nrf2 [73]. In addition, the application prospects of combination therapy in treating advanced HCC have also been recently discovered. The PTL nanocrystal delivery system was used in combination with sorafenib (Sora) to treat tumors in mice with HCC. The tumor inhibition rate reached 81.86%, far exceeding that of individual PTL and Sora, which means that the combination drug not only improves the poor water solubility of PTL but also enhances the therapeutic effect [74]. Next, it was reported that PTL also strengthened the drug sensitivity of gastric cancer cells to DDP and reverse the drug resistance of human gastric cancer cells via suppressing the STAT3 signaling pathway [75]. TMZ, the most applied chemotherapeutic drug to treat GBM after operation [76]. Inhibition of NF-κB leads to in anti-glioma activity and lowers TMZ-induced chemoresistance through down-regulating MGMT gene expression [77].DMAMCL, MCL, or PTL may not fully eradicate GBM. Thus, combination treatment of ACT001 with other therapies has also developed in recent years [57]. ACT001 and cisplatin act synergistically to suppress the PAI-1/PI3K/AKT pathway, increasing the apoptosis of glioma cells and overcoming cisplatin resistance in glioma cells [78]. DMAMCL can diffuse through the blood-brain barrier (BBB) and build up in the brain [79], resulting in decreased PD-L1 expression, while its side effects are required to be solved urgently. Thus, DMAMCL would probably be regarded as the best option in combination with TMZ for GBM treatment to reverse the immunosuppression and inhibit GBM cell immune escape caused by TMZ [80].Nowadays, L-3,4-Dihydroxyphenylalanine (L-DOPA) is applied in the treatment of Parkinson’s disease (PD) as the main agent but may cause serious side effects if used continuously. DMAMCL and low dose of L-DOPA were proved to be equivalent to the administration of L-DOPA in a high dose in PD in mice, suggesting that DMAMCL enhance the curative effect of L-DOPA on PD [81]. Combination treatment of MCL and radiotherapy can ameliorate the sensitivity of cancer tissues to radiotherapy and enhance the therapeutic effect of radiotherapy. MCL effectively cultivates radiosensitivities of p53-deficient non-small-cell lung cancer by inhibiting the HIF-1α pathway via promoting HIF-1α degradation [82]. MCL-mediated depletion of GSH reduces the occurrence of KLF4-mediated cisplatin resistance in breast cancer cells [83].


## 7. Conclusion

It has been widely recognized that inflammation could contribute to tumor formation and growth. The most potent example is carcinogens in colon cancer and inflammatory bowel disease. Many biological macromolecules have been discovered and used as anticancer and anti-inflammatory drugs to overcome these problems and infections. However, PLTs, the secondary metabolites or plant extracts specially derived fromTanacetum parthenium, have been widely used to treat cancer and inflammatory cells and could proliferate pathways such as NF-κB, STAT3, and MAPK. The current review summarized above that PLT could protect the normal cells from apoptosis, but induce apoptosis in the cancer cell. Therefore, the present review could be helpful in the future to establish and open more research directions.



---

*Source: 3744837-2022-07-18.xml*