암 치료에 대한 잠재적 보조제로서의 천연 화합물: 전임상 증거

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14816

BPS Publications

Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence

 

Table 1. Clinical trials for natural compounds or herbal medicines combining with chemotherapy

Recruitment statusNatural compoundsDrugsPhaseDiseaseTrial ID

Clinical trial for natural compound combinations
Unknown	Curcumin	Gemcitabine Celebrex	III	Pancreatic cancer	NCT00486460
+	+	+	+	Colon cancer	NCT00295035
Clinical trial for herbal products combinations
Completed	Teng-Long-Bu-Zhong-Tang	Oxaliplatin Capecitabine	II	Colon cancer	NCT01975454
	TCM	Cyclophosphamide Doxorubicin HCl	+	Breast cancer	NCT00028964
	+	Docetaxel Vinorelbine Gemcitabine	+	NSCLC	NCT01780181
	+	Vinorelbine Platinum-based chemotherapy	III	+	NCT01441752
	+	CDDP 5-FU	II	Peritoneal carcinomatosis	NCT02638051
	Jin Fu Kang	Docetaxel	+	NSCLC	NCT00260026
Recruiting	TCM	Adjuvant chemotherapy	+	Breast cancer	NCT03797248
	+	Standard chemotherapy protocols	I	NSCLC	NCT02737735
Enrolling by invitation	Yiqi-yangyin-jiedu decoction	Gefitinib	III	Lung cancer	NCT02929693
Active, not recruiting	PHY906	Sorafenib Tosylate	I	Liver cancer	NCT01666756
Unknown	+	Gefitinib Erlotinib Icotinib	NA	Pulmonary adenocarcinoma	NCT01745302
	+	Lotrozole	NA	Polycystic ovary syndrome	NCT01431352

• Note. For detail information about each clinical trial, see following website: https://clinicaltrials.gov/.
• Abbreviations: +, The same with above cell; 5-FU, 5-Fluorouracil; CDDP, cisplatin; NA, not applicable; NSCLC, non-small-cell lung cancer; TCM, traditional Chinese medicine.

Table 2. Herbal compounds act as an enhancer of cancer therapy

Structure subclassNatural compoundChemotherapeutic drugCancerSignal pathwayReferencea

Cell death via specific signalling pathway
Alkaloid	3,3′-Diindolylmethane	Cisplatin	Ovary	STAT3/Akt	(Zou, Xu, Li, Zhang, & Fan, 2018)
	Berberine	Radiation	Esophagus	Rad51	(Liu et al., 2011)
	Ethoxysanguinarine	Cisplatin	Lung	CIP2A	(Liu, Ma, Wen, Cheng, & Zhou, 2014)
	Melatonin	+	Liver	NF-κB/AP-2β	(Hao et al., 2017)
	Neferine	Doxorubicin	Lung	Fas/ROS	(Poornima, Kumar, Weng, & Padma, 2014)
	Noscapine	Cisplatin	Ovary	HIF-1α	(Su et al., 2011)
	Piperlongumine	Doxorubicin	Prostate	Carbonyl reductase 1	(Piska et al., 2019)
Capsaicinoid	Capsaicin	Radiation	Prostate	NF-κB	(Venier et al., 2015)
Diarylheptanoid	Curcumin	5-FU	Gastric	NF-κB	(Kang et al., 2016)
	+	Carboplatin	Lung	Akt/NF-κB	(Kang et al., 2015)
	+	+	Breast	FEN1	(Zou et al., 2018)
	+	+	Colorectal	endoG/NF-κB	(Wang, Liu, & Su, 2014)
	+	+	Lymphoma	Rad51, apoptosis-Caspase	(Zhao et al., 2018)
	+	+	Neuroblastoma	Uniquitin	(D'Aguanno et al., 2012)
	+	+	Ovary	c-Myb/STAT3/NF-κB	(Tian, Tian, Qiao, Li, & Zhang, 2019)
	+	Doxorubicin	Gastric	NF-κB	(Yu, Wu, Dai, Yu, & Si, 2011)
	+	Radiation	Prostate	miR-143	(Liu, Li, Wang, & Luo, 2017)
	+	Rhtrail	Breast	DR5/IAP	(Park, Cho, Andera, Suh, & Kim, 2013)
Diterpenoid	Adenanthin	1,25 dihydroxyvitamin D3	Leukaemia	Prx-1/C/EBP	(Wei et al., 2016)
	Cryptotanshinone	Cisplatin	Ovary	MMP-2 and MMP-9	(Jiang et al., 2017)
	+	Paclitaxel	Oral	JAK/STAT3 e-Cadherin/p53/β-catenin	(Wang et al., 2017)
Flavonoid	(−)-Epicatechin	Radiation	Pancreas/Glioma	Chk1/p21	(Elbaz, Lee, Antwih, Liu, Huttemann, & Zielske, 2014)
	Formononetin	Doxorubicin	Gastric	HDAC5	(Liu et al., 2015)
	Icariin	5-FU	Colorectal	NF-κB	(Shi et al., 2014)
	Luteolin	Cisplatin	Bile duct	PI3K/Akt/mTOR/SREP	(Lim, Yang, Bazer, & Song, 2016)
	Naringenin	Paclitaxel	Prostate	PI3K/Akt and MAPK	(Lim, Park, Bazer, & Song, 2017)
	WYC02	Cisplatin	Multi cancer	ATM	(Wang et al., 2012)
	Quercetin	Rhtrail	Breast	c-FLIP/DR5	(Manouchehri, Turner, & Kalafatis, 2018)
	Silibinin	5-FU	Colorectal	PI3K/MAPK/CTNNB1/nanog/CD44v6	(Patel et al., 2018)
Isoprenoid	Vitamine K2	+	Liver	NF-κB	(Zhang et al., 2011)
Macrolide	Elaiophylin	Cisplatin	Ovary	Cathepsin	(Zhao et al., 2015)
Monoterpenoid	Borneol	+	Oesophagus	PI3K/Akt	(Meng et al., 2018)
Organosulfur	Sulforaphane	Doxorubicin	Ovary	SFN, CA IX	(Pastorek et al., 2015)
Phenolic	Anacardic acid	Radiation	Prostate	γ-H2AX	(Yao et al., 2015)
	Caffeic acid	Metformin	Cervix	AMPK/TCA cycle	(Tyszka-Czochara, Konieczny, & Majka, 2017)
	+	+	+	SNAI1/MMP-9	(Tyszka-Czochara, Lasota, & Majka, 2018)
	Capsaicin	Docetaxel	Prostate	PTEN/PI3K/Akt/mTOR LKB1/AMPK	(Sanchez, Bort, Mateos-Gomez, Rodriguez-Henche, & Diaz-Laviada, 2019)
	Dicoumarol	Doxorubicin	Urinary tract	NADPH quinone oxidoreductase	(Matsui et al., 2010)
	Emodin	Tamoxifen	Breast	Ras/ERK PI3K/mTOR	(Tseng et al., 2017)
Polyyne	Falcarindiol	5-FU	Colorectal	ER stress	(Jin et al., 2012)
Susquiterpenoid	Heteronemin	Cytarabine	Leukaemia	Ras farnesylation	(Saikia et al., 2018)
	β-Eudesmol	Doxorubicin 5-FU	Bile duct	NADPH quinone oxidoreductase	(Srijiwangsa, Ponnikorn, & Na-Bangchang, 2018)
Phytosteroid	Polyphyllin D	Cisplatin	Ovary	18 unique genes	(Al Sawah et al., 2015)
	Tenacigenin B derivative	Paclitaxel	Ovary	Inhibit Cytochrome P450	(Xie et al., 2019)
Stilbenoid	Resveratrol	Cisplatin	Lung	Mitochondrial depolarization	(Ma et al., 2015)
	+	Doxorubicin	Breast	HSP-27	(Diaz-Chavez et al., 2013)
	+	+	+	Carbonyl reductase 1	(Ito et al., 2013)
Tetrahydrofuran	Acetogenin	Doxorubicin	Ovary	Mitochondrial complex I	(Tormo et al., 2003)
Tripyrrole	Prodigiosin	Paclitaxel	+	Survivin	(Ho et al., 2009)
	+	Doxorubicin	Oral	Doxorubicin accumulation	(Lin & Weng, 2018)
Triterpenoid	Brusatol	5-FU	Pancreas	e-cadherin/Twist/vimentin/NF-κB	(Lu, Lai, Leung, Leung, Li, & Lin, 2017)
Triterpenoid	Celastrol	Cisplatin	Lung	FANCD2	(Wang, Liu, Cheng, & Zhou, 2015)
	+	Tanespimycin	Glioblastoma	P62, Hsp72, Hsp90	(Boridy, Le, Petrecca, & Maysinger, 2014)
Xanthonoid	Formononetin	Metformin	Breast	ERK1/2/Bcl-2	(Xin, Wang, Ren, & Guo, 2019)
Via apoptosis or autophagy
Alkaloid	Berberine	Sorafenib	Liver	Apoptosis-Intrinsic	(Huang et al., 2018)
	Indole-3-carbinol	Cisplatin	Ovary	+	(Taylor-Harding et al., 2012)
	+	Doxorubicin	Cervix	+	(Adwas, Elkhoely, Kabel, Abdel-Rahman, & Eissa, 2016)
Carotenoid	Bixin	+	Acute leukaemia	Apoptosis	(Santos, Almeida, Antunes, & Bianchi, 2016)
Diarylheptanoid	Curcumin	Cisplatin	Lung	Apoptosis-Intrinsic	(Baharuddin et al., 2016)
	+	+	Oral	Apoptosis-Intrinsic	(Chen et al., 2018)
	+	Sorafenib	Liver	Apoptosis-Intrinsic	(Bahman, Abaza, Khoushiash, & Al-Attiyah, 2018)
Diterpenoid	Crassin	Doxorubicin	Breast	Apoptosis-ROS	(Richards, Vellanki, Smith, & Hopkins, 2018)
	Ent-kaurane-type diterpenoids	+	Liver	Apoptosis	(Pham, Iscache, Pham, & Gairin, 2016)
Flavonoid	Eupatorin	+	Colorectal	Apoptosis-Intrinsic	(Namazi Sarvestani, Sepehri, Delphi, & Moridi Farimani, 2018)
	Phloretin	Cisplatin	Lung	Apoptotic/MMPs	(Ma, Wang, Nan, Li, Wang, & Jin, 2016)
	Salvigenin	Doxorubicin	Colorectal	Apoptosis-Intrinsic	(Namazi Sarvestani, Sepehri, Delphi, & Moridi Farimani, 2018)
Lignan	Enterolactone	+	Breast	Apoptosis	(Di, De Silva, Krol, & Alcorn, 2018)
	Secoisolariciresinol	+	+	+	(Di, De Silva, Krol, & Alcorn, 2018)
Organosulfur	Lipoic acid	Temozolomide	Colorectal	Autophagy	(Goder et al., 2015)
	Alyssin	5-FU	Colorectal	Apoptosis-Extrinsic	(Milczarek et al., 2018)
Phenolic	Embelin	Photodynamic therapy	Ehrlich	Apoptosis-Intrinsic	(Joy, Nishanth Kumar, Soumya, Radhika, Vibin, & Abraham, 2014)
Phenolic	Nordihydroguaiaretic acid	Cisplatin	Breast	ROS	(Mundhe, Kumar, Ahmed, Jamdade, Mundhe, & Lahkar, 2015)
Phenolic	Osthole	+	Lung	Apoptosis-Intrinsic	(Xu et al., 2013)
Sesquiterpenes	Trans-nerolidol	Doxorubicin	Breast	doxorubicin accumulation	(Hanusova et al., 2017)
	β-Caryophyllene oxide	+	+	+	(Hanusova et al., 2017)
	β-Elemene	Cisplatin	Lung/Brain/Breast/ Cervix/Ovary/Colorectal	Apoptpsis-Intrinsic & Extrinsic	(Li et al., 2013)
Stilbenoid	Resveratrol	Sorafenib	Liver	Apoptosis-Intrinsic	(Bahman, Abaza, Khoushiash, & Al-Attiyah, 2018)
Triterpenoid	Withaferin A	Radiation	Lymphoma	Apoptosis-ROS, Bcl-2	(Yang, Choi, Kim, Choi, & Kwon, 2011)
	Acetyl-11-keto-β-boswellic acid	+	Glioblastoma	Apoptosis-Intrinsic	(Conti et al., 2018)
Xanthonoid	Forbesione	5-FU	Bile duct	Apoptosis-Intrinsic	(Boueroy et al., 2017)
	Gambogic acid	Doxorubicin	Ovary	Apoptosis-ROS	(Wang & Yuan, 2013)
	Kaempferol	Sorafenib	Liver	Apoptosis-Intrinsic	(Bahman, Abaza, Khoushiash, & Al-Attiyah, 2018)
Reducing chemoresistance via specific mechanism
Alkaloid	Aaptamine	Cisplatin	Embryonal carcinoma	myc, p53, eIF5A hypusination	(Dyshlovoy et al., 2014)
	Demethyloxyaaptamine	+	+	TNF	(Dyshlovoy et al., 2014)
	Isoaaptamine	+	+	myc, p53, TNF	(Dyshlovoy et al., 2014)
	Sinapine	Doxorubicin	Colorectal	FGFR4-FRS2α-ERK1/2	(Guo, An, Feng, Liu, Wang, & Zhang, 2014)
Diarylheptanoid	Curcumin	Cisplatin	Lung	FA/BRCA	(Chen, Li, Jiang, Lan, & Chen, 2015)
	+	+	Ovary	MEG3, miR-214	(Zhang, Liu, Xu, & Li, 2017)
	+	+	+	miR-186	(Tang, Zhang, & Du, 2010)
Flavonoid	Isoliquiritigenin	+	Oral	ALDH1, CD44, GRP78	(Hu, Yu, Hsieh, Liao, Lu, & Chu, 2017)
	Tectorigenin	Paclitaxel	Ovary	Akt/iκB/IKK	(Yang et al., 2012)
	Wogonin	Doxorubicin	Breast	Nrf2	(Zhong et al., 2013)
Lignan	Silybin	+	Colon	GLUT1	(Catanzaro et al., 2018)
Nucleoside	Clitocine	+	Liver	NF-κB	(Sun et al., 2012)
Organosulfur	Sulforaphane	Cisplatin	Ovary	HIF-1α	(Pastorek et al., 2015)
Phenol	Phenylethyl isothiocyanate	+	In vivo	Mcl-1 glutathionylation	(Li et al., 2016)
	Emodin	Doxorubicin	Lung	Anthracycline reductases	(Hintzpeter, Seliger, Hofman, Martin, Wsol, & Maser, 2016)
Steroid	Cucurbitacin b	+	Gastric	CIP2A/PP2A/mTORC1	(Liu et al., 2017)
Triterpenoid	Adcx	Paclitaxel	Liver	Akt/autophagy	(Sun et al., 2017)
	Polyphyllin I	Erlotinib	Lung	IL-6/STAT3	(Lou, Chen, Zhu, Deng, Wu, & Wang, 2017)
Via inhibiting drug efflux
Alkaloid	Cinchonine	Paclitaxel	Uterine		(Lee et al., 2011)
	Hydrocinchonine	Paclitaxel	Uterine		(Lee et al., 2011)
	Quinidine	+	+		(Lee et al., 2011)
Diarylheptanoid	Curcuminoid	Doxorubicin	Leukaemia		(Xu, Tian, & Shen, 2013)
Diterpenoid	Tanshinone IIA	Doxorubicin	Gastric		(Xu et al., 2018)
Flavonoid	Biochanin A	Daunorubicin	Breast		(Zhang, Sagawa, Arnold, Tseng, Wang, & Morris, 2010)
	Glabridin	Doxorubicin	+		(Qian et al., 2019)
Lignan	Matairesinol	Doxorubicin	Colon		(Su, Cheng, & Wink, 2015)
	+	+	Leukaemia		(Su, Cheng, & Wink, 2015)
Monoterpene	Borneol-peg-np	Paclitaxel	Ovary		(Zou et al., 2017)
Triterpenoid	Maslinic acid	+	Diarthrosis/smooth muscle		(Villar et al., 2014)
	Oleanolic acid	+	+		(Villar et al., 2014)
	Ursolic acid	Doxorubicin	Breast		(Zong, Cheng, Liu, Pi, Liu, & Song, 2019)
Xanthone	Forbesione	Doxorubicin	Bile duct	NF-κB & p-Glycoprotein	(Hahnvajanawong et al., 2014)
	Isomorellin	+	+		(Hahnvajanawong et al., 2014)
Xanthonoid	Mangiferin	+	Breast	p-Glycoprotein, MRP-1, BCRP	(Louisa, Soediro, & Suyatna, 2014)
	Gambogic acid	Multidrugs	Multi-cancer	p-Glycoprotein	(Wang et al., 2013)

• Note. Intrinsic: Bcl-2/Bcl-XL/caspase-3, 9; Extrinsic: DR/Bid/caspase-3, 7, 8; +, the same with above cell.

Recent-known mechanism of chemoresistance

 

Table 3. Natural compounds as potential adjuvants to cancer therapy: Unpredictable adverse events

Herbal compoundsChemotherapeutic drugsCancer or normal cell typeAdverse effect and relevant mechanismReferencea

Curcumin	Doxorubicin	Cardiac muscle cells	Apoptosis-ROS	(Hosseinzadeh, Behravan, Mosaffa, Bahrami, Bahrami, & Karimi, 2011)
	Etoposide	Cervix/Breast/Colorectal	Offset cancer cell death via DDR/γ-H2AX	(Saleh, El-awady, Eissa, & Abdel-Rahman, 2012)
Acetyl-L-carnitine	Taxane	Breast cancer	Increase peripheral neuropathy	(Hershman et al., 2013)
Chokeberry	Trabectedin	Liposarcoma	Induce rhabdomyolysis	(Strippoli, Lorusso, Albano, & Guida, 2013)
Bu Zhong Yi Qi Wan	Temozolomide/radiation	Glioblastoma	Induce acute liver toxicity	(Melchardt et al., 2014)

• a For Reference list, see Data S2.

Putative mechanism of natural compounds in chemotherapeutic synergism