암 연구에서의 식물 유래 천연 제품

 

https://www.mdpi.com/1420-3049/25/22/5319/htm

Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation

<Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation>

Mechanisms of action of natural products and their analogues.

CompoundsCancer Cell Line and Animal Model Mechanisms of Action Classes of Analogues Mechanisms of Action

Curcumin		Induced ligand (TRAIL) apoptotic pathways via upregulating death receptor 5 [31]. Initiated Fas-mediated apoptotic pathway by activating caspase-8 [32]. Upregulate Bax expression and suppress Bcl-2 through activation of p53 [33]. In activation of JAK/STAT signaling [14]. Inhibition of MMP-9; downregulating endothelial cell marker; and inhibition of STAT3 and NF-κB and activated caspase-3 [19].		Showed five-fold improvement in the potency and enhanced apoptosis via caspase-3 induction 19.9%, compared to the curcumin [393]. Enhanced cancer cell apoptosis through disruption of mitochondria function, prevented TrxR activity, and increased Bax/Bcl-2 production [394].
Resveratrol		Inhibited cell growth by activating caspase-3 and caspase-9, upregulating of Bcl-2 associated X protein, and inducing expression of p53 [52]. Induced cell apoptosis and G1 phase arrest via suppression of AKT/STAT3 signaling pathway [53]. Improved apoptotic and oxidant effects of paclitaxel by activating TRPM2 channel [54]. Reduced vascular endothelial growth factor (VEGF) expression [55]. Inhibited metastasis by affecting IL-1β, TNF-α, vimentin, N-cadherin, and CTA-2 expressions [56]. Upregulating p53 and Bax expression, increasing Bcl-2 activity, and inducing caspase-3 activation. Decreased tumor size by downregulating E6 and tumor protein levels [57],		Induced apoptosis by inhibition of topoisomerase II [395]. Improved anticancer properties of the natural resveratrol by inhibiting cell growth, preventing metastasis, and triggering cancer cells apoptosis [396]. Induced cell cycle arrest in S phase via modulation of cyclin A1/A2 and promoted cell death through upregulation of Bax/Bcl2 [397].
EGCG		Inhibited the metastatic activity by downregulation of protein expression of MMP-2 through modulation of the Src signaling pathway [82]. Downregulated cyclinD1 and upregulated cell cycle inhibitors LIMD1, RBSP3, and p16 at G1/S phase of the cell cycle [83]. Enhanced apoptosis by activating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling [85]. Inhibited cell growth through matrix metalloproteinase (MMP)-2- and -9-independent mechanisms [89]. Suppressed tumor growth in TRAMP mice and decreased tumor-derived serum PSA [91]. Inhibited cancer tumors in PDX model by suppressing the expression of NF-κB regulated genes [93].		Improved cancer cell death by inducing apoptosis and inhibition of FASN activity [398]. Inhibits cell proliferation via downregulation of cellular proteasome [399]. Prevents tumor growth by inhibiting the phosphorylation of EGFR, as well as inducing apoptosis [400].
		Induced apoptosis and prevented cell migration through upregulating of SHP-1 and inhibiting STAT3 activation [107]. Attenuated tumor growth in the nude mouse model of cholangiocarcinoma [107]. Inhibition of NF-κB signaling pathway [108]. Upregulates miR-486-3p and increases chemosensitivity to temozolomide [110]. Inhibition of cytokine release and upregulation of p53 activity [109]. Inhibiting ornithine decarboxylase, a rate-limiting enzyme in cell proliferation of neuroblastoma, and inducing cell apoptosis [111]. Suppresses melanoma cell growth via increasing cyclin D1 and reducing MMP-9 mRNA expression [112]. Inhibiting human glioblastoma proliferation by stimulating S and G2/M phase cell cycle arrest, apoptosis, and autophagy [113]. Reducing growth and metastasis through upregulation of miR-383-5p and downregulation of ERBB4 [114].		Increased caspase-3 activity and modulated Bax/Bcl2 expression [401].
Emodin		Cell cycle arrest, apoptosis, and the promotion of the expression of hypoxia-inducible factor 1α, glutathione S-transferase P,N-acetyltransferase, and glutathione phase I and II detoxification enzymes, while inhibiting angiogenesis, invasion, migration, chemical-induced carcinogen-DNA adduct formation, HER2/neu, CKII kinase, and p34cdc2 kinase [136]. Inhibits tumor-associated angiogenesis through the inhibition of ERK phosphorylation [137]. Downregulates the expression of survivin and β-catenin, inducing DNA damage and inhibiting the expression of DNA repair [136,138]. Inhibits the activity of casein kinase II (CKII) by competing at ATP-binding sites [136,139]. Upregulates hypoxia inducible factor HIF-1 and intracellular superoxide dismutases and boosts the efficacy of cytotoxic drugs [140,141]. Decreases the expression of MDR-1 (P-gp), NF-κB and Bcl-2 and increasing the expression levels of Bax, cytochrome-C, caspase-9 and -3, and promoting cell apoptosis [142]. Downregulates both XIAP and NF-κB and enhances apoptosis [143,144]. ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1 in overactivated HIF-1 cells [146].		Suppressed ErbB2 activity, triggered G2 arrest, downregulated the expression of (Bcl-xl and Bcl-2), and induced caspase-3 and caspase-9 [402].
Thymoquinone		Upregulation of p21cip1/waf1 and a downregulation of cyclin E, and associated with an S/G2 arrest of the cell cycle [154]. Induced the G0/G1 cell cycle arrest, increased the expression of p16, decreased the expression of cyclin D1 protein, inactivated CHEK1, and contributed to apoptosis [155,156]. Reduced the elevated levels of serum TNF-α, IL-6, and iNOS enzyme production [158]. Reducing the NO levels by downregulation of the expression of iNos, reducing Cox-2 expression, and consequently generating PGE2 and reducing PDA cells synthesis of Cox-2 and MCP1 [159,160]. Noticeably reduced the phosphorylation of EGFR at tyrosine -1173 residues and JAK2 [161]. Elevation of PPAR-γ activity and downregulation of the gene’s expression for Bcl-2, Bcl-xL, and surviving [162]. Downregulation of the expression of STAT3-regulated gene [163]. Activation of caspases 8, 9, and 7 in a dose-dependent manner and increases the activity of PPAR-γ [165,167]. Decrease of expressions of CYP3A2 and CYP2C 11 enzymes [171]. Increase of the PTEN mRNA [173]. Suppresses androgen receptor expression and E2F-1		Inhibited cancer cell growth two-fold, compared to the natural thymoquinone [403]. Suppresses cell viability and reduces the pro-survival and pro-angiogenic molecules COX-2 [404].
Genistein		Inhibits cyclooxygenase-2 (COX-2) directly and indirectly by suppressing COX-2-stimulating factors like activated protein-1 (AP-1) and Nf-κb [175]. Inhibits CDK by upregulating p21; suppresses cyclin D1, ultimately inducing G2/M cell cycle arrest; and decreases tumor cell progressions [175,184,186,187,188]. Downregulates the expression levels of matrix metalloproteinase-2 (MMP-2) [175,189,190]. Inhibits several targets, including Cyclin D1, MMP, VEGF, Bcl-2, uPA, and Bcl-XL [175]. Influences metastasis and induces apoptosis by inhibiting Akt, as well as NF-κB cascades [175,191]. Inhibits histone deacetylase (HDAC) enzymes, which are responsible of regulating histone acetylation of DNA [175]. Inhibition of Hsp90 chaperones [197].		Reduces expression of c-Myc and P13k/AKT [405].
Parthenolide		It mediated STAT3 inhibition, inducing the expression of death receptors and, hence, an apoptotic pathway [216]. Activation of p53 and the increased production of reactive oxygen species (ROS) [199,210], along with reduced glutathione (GSH) depletion [214]. Targets mitochondrial thioredoxin reductase to elicit ROS-mediated apoptosis [217]. Interferes with microtubule formation and prevents proliferation of malignant cells [218]. Induces thrombopoiesis through the inhibitory activity of NF-κB and consequently renders cancer cells prone to undergo apoptosis [219]. Impairs focal adhesion kinase-dependent signaling pathways and, hence, the cell proliferation, survival, and motility [220].		Reduced cancer cell viability through activation of caspase-3 and suppression of NF-κB [406]. Induces apoptosis via stimulation of ROS and inhibition of NF-κB [407].
Luteolin		Activates both the extrinsic and intrinsic apoptosis pathways and increases the expression of death receptor 5 [243]. Inhibits cell growth and induces G2 arrest and apoptotic cell death via activating JNK and inhibiting translocation of NF-κB [244]. Suppressed proliferation and survival of cancer cells by inhibition of angiogenesis through blocking activation of the VEGF receptor and its downstream molecule PI3K/Akt and PI3K/p70S6 kinase pathways [245]. Inhibitions of wide panel of receptor tyrosine-kinases activity, such as human epidermal growth-factor receptor 2 (HER-2), insulin-like growth factor (IGF), and epidermal growth-factor receptor (EGFR) [246]. Increased the expression of genes related to apoptosis and stress response within LC540 tumor Leydig cells [249].
Quercetin		Reduced the expression of epidermal growth factor receptor (EGFR), tyrosine kinases involved in the development of a wide variety of solid tumors, resulting in the inhibition of cell growth and the induction of apoptosis [272]. Increased the expression of death receptor 5 (DR5) resulting in stimulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and subsequent cancerous cells apoptosis [273]. Direct targeting of Raf and MEK in Raf/MEK/ERK cascade, which is important pathway in neoplastic transformation [274]. Activation of caspases cascade; increases the level of caspase-3 and -9 and then higher expression of proapoptotic Bcl-2 family members and lower levels of antiapoptotic Bcl-xL that contributed directly to the apoptotic process [275]. Interaction of quercetin with DNA directly as one of the mechanisms for inducing [276].		Stimulates cell cycle arrest in S phase and activates ROS-dependant apoptosis pathway [408]. Triggered apoptosis via suppression of topoisomerases and activation of ROS pathway [271].
Paclitaxel		Stabilization of cellular microtubules through binding β-tubulin subunit and inhibiting their depolymerization leading to block in the progress of mitotic division and prohibit cell division to ultimately cause apoptosis [307]. Causes cell death due to chromosome miss-aggregation on multipolar spindles where the resultant daughter cells are aneuploid, and a portion of these die due to loss of one or more essential chromosomes [308]. Targets the mitochondria and inhibits the function of the apoptosis inhibitor protein B-cell Leukemia 2 (Bcl-2) [309].		Disruption of microtubular depolymerization and modulation of bcl-2 and bcl-xL gene expression [409].
		Inhibition of polymerization of the microtubules through binding with the tubulin. This produces an arrest in G2/M phase and induces apoptosis [325]. Inhibitor of topoisomerase II [326]. High affinity to chromatin; binding of vincristine alters chromatin structure that perturbs histone-DNA interaction and possibly removal/displacement of the histones from DNA is occurred resulting in increasing of its cytotoxic effect [327].		Inhibition of cell division via interaction with tubulin formation, resulting in mitotic arrest or cell death [410].
Bromelain		Increases the expression of p53 and Bax activators genes of apoptosis in cancerous cells, and promotes apoptotic cell death in tumors [350]. Induced apoptosis via activating both caspase dependent and independent pathways [351]. Diminished the expression of the cell cycle regulatory proteins cyclin A, cyclin B, and cyclin D, resulting in G1 arrest [352]. Inhibition extracellular signal regulated protein kinase (ERK1/2) and p38 mitogen-activated protein kinase (MAPK), besides the decrease in Cox-2 expression and inhibition of NF-κB pathway [353]. Antiangiogenic effect by interfering with VEGF [354,355]. Stimulates ROS, and this would have a direct impact on the modulation of signaling in cancer cells, leading to tumor-cell-killing properties [334]. Upregulation of c-Jun N-terminal kinase and p38 kinase [357].
Boswellic acid		Inhibition of topoisomerases I and II, leading to apoptosis in different cell lines [376,377]. Downregulation of G1 phase cyclins and cyclin-dependent kinases (CDK) [378]. Induced apoptosis accompanied by activation of caspase-3, -8, and -9, resulting in expression of DR4 and DR5 [379,380,381]. Suppressed tumor growth through inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGFR2) signaling pathway [382]. Prohibited the phosphorylation of extracellular-signal-regulated kinase-1 and -2 (Erk-1/2) and impaired the motility of cancer cells; Erk pathway plays a crucial role in signal transduction and tumorigenesis [383]. Inhibiting autophagy through regulating the ERK and P53 signaling pathways [384]. Suppressed TNF-induced invasion through inhibition of NF-κB regulated gene expression [385]. DNA damage response accompanied by impairment of DNA repair genes [386].		Induce cancer cell death by promoting DNA fragmentation [410].

표 2. 상업적으로 승인된 표적 전달 시스템 및 활성 구성요소.

상표명활성 물질약물 전달 시스템적응증

리푸수 ®	파클리탁셀	레시틴/콜레스테롤 리포솜	난소암, 유방암, 비소세포폐암, 위암, 두경부암 치료
아브락산 ®	파클리탁셀	나노입자 알부민 결합	췌장의 전이성 선암 및 유방암 [ 658 ]
오팍시오 ®	파클리탁셀	고분자 기반 나노 제형	교모세포종의 치료 [ 699 ]
마르키보 ®	빈크리스틴	스핑고미엘린/콜레스테롤(SM/Chol) 리포솜	재발성 ALL을 가진 성인의 치료 [ 665 ]
테라커민 ®	커큐민	가티검과 글리세린을 이용한 콜로이드 분산	건강 삶의 질 향상 및 항산화 및 항염 작용 [ 700 ]
메리바 ®	커큐민	커큐미노이드 및 포스파티딜콜린 파이토솜	고형암 환자의 삶의 질 향상, 항염 효과 [ 701 ]

ALL = 급성 림프모구 백혈병.