Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics

Apaya, Maria Karmella; Chang, Mu‐Chieh; Shyur, Lie‐Fen

doi:10.1016/j.pharmthera.2016.03.001

Cited by 51 publications

(31 citation statements)

References 173 publications

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“…In addition, the anoectochilus formosanus and a schisandra polysaccharides isolated from Schisandra chinensis , were found to promote the M1 differentiation of TAM (Kuan et al, 2012). Recently, some plant natural products or phytoagents, including terpenoids, phenolics, plant-derived lipids, alkaloids and PHY906 (a multi-herb formulation), have also highlighted and summarized for their effects on the oxylipin dynamics in a defined tumor microenvironment (Apaya et al, 2016). These studies on natural compounds have brought into clarity the poly-pharmacological nature of phyto agents, which can be thought of as “multiple targets, multiple effect and complex disease”.…”

Section: Regulation Of Immune Cells In the Tumor Microenvironment By mentioning

confidence: 99%

Phytochemicals Approach for Developing Cancer Immunotherapeutics

2017

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Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy.

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Section: Regulation Of Immune Cells In the Tumor Microenvironment By mentioning

confidence: 99%

Phytochemicals Approach for Developing Cancer Immunotherapeutics

2017

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“…The cytotoxic activity of these plants could arise due to the occurrence of isoquinoline alkaloids in P. marginatus as well as cucurbitacins in I. sonorae, as is described in the scientific literature. Whereas single targeted chemotherapeutic drugs commonly lack efficacy and invoke drug resistance and adverse effects in cancer patients, traditional herbal medicines are seen as bright prospects for treating complex diseases, such as lymphoblastic leukemia, in a systematic and holistic manner [55]- [57]. Further studies on the mechanisms of biological effects by which the extract exerts their cytotoxic effects are necessary.…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic Effect of Methanol Extracts and Partitions of Two Mexican Desert Plants against the Murine Lymphoma L5178Y-R

Quintanilla-Licea¹,

Gómez-Flores²,

Samaniego-Escamilla³

et al. 2016

AJPS

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Pachycereus marginatus (DC.) Britton & Rose and Ibervillea sonorae (S. Watson) Greene have been used in the Mexican traditional medicine for the treatment of various diseases, including cancer. The present study aims to investigate the cytotoxic activity of these plants against a murine lymphoma. Soxhlet extraction of dried and powdered plant material was performed with methanol. Also, a further partitioning of these methanolic extracts with hexane and ethyl acetate was achieved. The in vitro cytotoxic activity against the murine lymphoma L5178Y-R cell line was assessed via the colorimetric MTT assay. The methanol extract from P. marginatus exhibited high cytotoxic activity (up to 94%) at concentrations ranging from 3.9 to 500 µg/mL; however, hexane and ethyl acetate partitions from this methanolic extract showed lower but significant (p < 0.05) concentration-dependent cytotoxicity (hexane partition up to 94% at 500 µg/mL; ethyl acetate partition up to 94% at 65.5 µg/mL). The methanolic extract and partitions derived from I. sonorae also showed significant (p < 0.05) and concentration-dependent cytotoxicity against L5178Y-R cells at concentrations ranging from 7.81 to 500 µg/mL (methanolic extract up to 63% at 500 µg/mL; hexane partition up to 76% at 250 µg/mL; ethyl acetate partition up to 73% at 500 µg/mL). These results demonstrate that the methanol extracts and partitions from P. marginatus and I. sonorae possess significant cytotoxic activity against the murine lymphoma L5178Y-R and validate the ethnobotanical use of these plants for the treatment of diseases consistent with cancer symptomatology. Previous scientific reports describe the isolation of isoquinoline alkaloids of P. margi-* Corresponding author. R. Quintanilla-Licea et al. 1522natus as well as cucurbitacins from I. sonorae, phytochemicals that could be responsible for their observed cytotoxic activity in this research. The direct extraction with methanol of medicinal plants allows extracting of both high and low-polarity compounds, contrary to the simple extraction with water that only allows obtaining compounds of high polarity. The subsequent partition of the methanol extract with a solvent of low polarity (hexane) and another of medium polarity (ethyl acetate) allows making a preliminary fractionation of the bioactive molecules present in the plant that will facilitate the bioguided chromatographic isolation of the pure compounds responsible for the biological activity of the plant.

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“…23,24 We hypothesized that the bioefficacy of dLGG against metastatic lung melanoma might be through modulating circulating oxylipin production and dynamics. 23,24 We hypothesized that the bioefficacy of dLGG against metastatic lung melanoma might be through modulating circulating oxylipin production and dynamics.…”

Section: Oxylipin Metabolome In Mouse Serummentioning

confidence: 99%

“…Oxylipins play multiple roles as mediators in the development of various cancers, including melanoma. 23,24 We hypothesized that the bioefficacy of dLGG against metastatic lung melanoma might be through modulating circulating oxylipin production and dynamics. Here, we established an oxylipin metabolomics platform and analyzed 47 oxylipin species and their expression levels in mice sera by using UPLC-MS/MS in a multiple reaction monitoring (MRM) model.…”

Section: Oxylipin Metabolome In Mouse Serummentioning

confidence: 99%

Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF‐α‐mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice

Yang

Chang

et al. 2018

Intl Journal of Cancer

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This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2-di-O-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16 melanoma. dLGG-20 (p.o. dLGG 20 mg/kg) and anti-cancer drug CP-2 (i.p. cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91 and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG-20 and CP-2 treatment prolonged mouse mean survival time. dLGG-20 treatment significantly inhibited the expression levels of several molecular markers, that is, PCNA, MMP2, COX-2, VEGF, vimentin, snail, TGF-β, β-catenin, TNF-α, PD-1 and PD-L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8 + Tc cell recruitment in the lung microenvironment was observed in dLGG-20-treated mice. A LC/MS-based comparative oxylipin metabolomics study showed that dLGG-20 treatment significantly induced (5.0- to 12.8-fold) the 12/15-LOX catalyzed oxylipin products in mouse serum including 17-HDHA from DHA, 15-HEPE from EPA, 8- and 12-HETEs from AA, and CYP450-derived 20-HETE from AA. CP-2 treatment increased 12/15-LOX derived 8-, 11- and 12-HETEs from AA, and CYP450 derived 11,12-EET from AA ad 9,10-DHOME from LA by 5.3- to 8.1-fold. Of note, dLGG and 17-HDHA were more effective than CP in preventing B16 melanoma cell-induced pulmonary vascular permeability in mice through inhibition of TNF-α production, up-regulation of tight junction proteins claudin1 and ZO-2 and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma.

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Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics

Cited by 51 publications

References 173 publications

Phytochemicals Approach for Developing Cancer Immunotherapeutics

Phytochemicals Approach for Developing Cancer Immunotherapeutics

Cytotoxic Effect of Methanol Extracts and Partitions of Two Mexican Desert Plants against the Murine Lymphoma L5178Y-R

Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF‐α‐mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice

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