Studies Proving Synergy among Terpenes, Flavonoids, and other Compounds

Studies Finding Synergistic Effects (with citations, may include additive or combinative effects)

"Based on the dose-dependent antennal and behavioural responses of E. obliqua to these bioactive compounds, myrcene, ?-terpinene, linalool, cis-verbenol, camphor and verbenone were found to play a key role in repelling the moths, and the mixture that included all eight compounds was significantly more effective."

[Zhang, Zhengqun, Lei Bian, Xiaoling Sun, Zongxiu Luo, Zhaojun Xin, Fengjian Luo, and Zongmao Chen. "Electrophysiological and behavioural responses of the tea geometrid Ectropis obliqua (Lepidoptera: Geometridae) to volatiles from a non-host plant, rosemary, Rosmarinus officinalis (Lamiaceae)." Pest Management Science 71.1 (2015): 96-104.]

"However, significant cytotoxicity was observed when cells were cotreated with limonene and linalyl acetate whereas no other associations were effective. Only cotreatment, but not the single exposure to limonene and linalyl acetate, replicated distinctive morphological and biochemical changes induced by BEO (bergamot essential oil)."?

[Russo R, Ciociaro A, Berliocchi L, Cassiano MG, Rombolà L, Ragusa S, Bagetta G, Blandini F, Corasaniti MT.?Implication of limonene and linalyl acetate in cytotoxicity induced by bergamot essential oil in human neuroblastoma cells.?Fitoterapia. 2013 Sep;89:48-57. doi: 10.1016/j.fitote.2013.05.014. Epub 2013 May 23]

"Overall, the present investigation revealed that the major components of P. roseum and specially the whole essential oil could be helpful in developing novel and safe mosquito control tools and also offer an environmentally safe and cheap tool for reducing Cx. pipiens mosquito populations."

[Tabari MA, Youssefi MR, Esfandiari A, Benelli G.?Toxicity of ?-citronellol, geraniol and linalool from Pelargonium roseum essential oil against the West Nile and filariasis vector Culex pipiens (Diptera: Culicidae).?Res Vet Sci. 2017 Oct;114:36-40. doi: 10.1016/j.rvsc.2017.03.001. Epub 2017 Mar 6.]

"The three compounds alone inhibited cell proliferation in a dose-dependent fashion, while their pairwise combination produced synergistic antiproliferative effects in both cell lines."

[Rodenak Kladniew, Boris, Mónica Polo, Sandra Montero Villegas, Marianela Galle, Rosana Crespo, and Margarita García de Bravo. "Synergistic antiproliferative and anticholesterogenic effects of linalool, 1,8-cineole, and simvastatin on human cell lines." Chemico-Biological Interactions 214 (2014): 57-68.]

"In this study, diverse essential oils were initially investigated for anti-biofilm activity against C. albicans strains, and cascarilla bark oil and helichrysum oil and their components a-longipinene (a major constituent of both) and linalool were found to markedly inhibit biofilm formation without affecting planktonic cell growth. Moreover, a-longipinene and linalool were found to synergistically reduce biofilm formation."

[Manoharan RK, Lee JH, Kim YG, Kim SI, Lee J.?Inhibitory effects of the essential oils a-longipinene and linalool on biofilm formation and hyphal growth of Candida albicans.?Biofouling. 2017 Feb;33(2):143-155. doi: 10.1080/08927014.2017.1280731. Epub 2017 Feb 3.]

"On the other hand, the nematicidal activity of T. mastichina EO did not correlate with that of its major components alone (1,8-cineole, terpineol, linalool and b-pinene) or in binary mixtures of 1,8-cineole with other compounds. Therefore, the contribution of each component to the activity of an EO follows a complicated pattern of interactions (Ntalli et al. 2010) including synergistic and/or antagonistic interactions that contribute to the overall toxicity of the oil (Lahlou 2004)."

[Andrés, Maria, Azucena González-Coloma, Jesus Sanz, Jesus Burillo, and Paula Sainz. "Nematicidal activity of essential oils: a review." Phytochemistry Reviews 11.4 (2012): 371-390.]

"In S. aureus, the linalool with Imipenem association showed a synergistic effect (FIC = 0.0625); while with ciprofloxacin, the linalool showed additivity (FIC = 0.75). In P. aeruginosa, the Imipenem/linalool association was synergistic for both the ATCC and clinical strains (FIC = 0.0625). We conclude that Linalool associated with existing standard antibiotics may increase antibacterial effectiveness, resulting in synergistic activity against bacterial strains of clinical importance."

[Silva V.A., Sousa, J.P., Guerra F.Q.S., Pess?a H.L.F., Freitas A.F.R., Coutinho, H.D.M., Alves L.B.N, Lima E.O.?Antibacterial Activity of the Monoterpene Linalool: Alone and in Association with Antibiotics Against Bacteria of Clinical Importance?International Journal of Pharmacognosy and Phytochemical Research 2015; 7(5); 1022-1026]

"The isolated sesquiterpenes are the major active principles responsible for the potent mosquitocidal activity, but the synergistic action of other constituents of the oil cannot be disregarded, as the whole oil is more effective than the individual compounds."

[Ravi Kiran, S., and P. Sita Devi. "Evaluation of mosquitocidal activity of essential oil and sesquiterpenes from leaves of Chloroxylon swietenia DC.." Parasitology Research 101.2 (2007): 413-418.]

"When the oils (from Laurus nobilis leaves and seeds) were added to a suboptimal concentration of the commercial drug, cytosine arabinoside, a clear synergic effect was observed."

[Saab AM, Tundis R, Loizzo MR, Lampronti I, Borgatti M, Gambari R, Menichini F, Esseily F, Menichini F.?Antioxidant and antiproliferative activity of Laurus nobilis L. (Lauraceae) leaves and seeds essential oils against K562 human chronic myelogenous leukaemia cells.?Nat Prod Res. 2012;26(18):1741-5. doi: 10.1080/14786419.2011.608674. Epub 2011 Oct 21.]

"These results suggest that the TPL/DCF (terpinolene/diclofenac) association had a synergistic anti-inflammatory and analgesic effect without causing apparent gastric injury, and that the serotonergic system may be involved in the antinociceptive effect of this association."

[Macedo, E M A et al. “Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation.” Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas vol. 49,7 (2016): e5103. doi:10.1590/1414-431X20165103]

"Compounds were also used as binary mixtures and tested for synergy, using toxicity and feeding inhibition parameters. The data showed that thymol and a-terpineol synergized the effects of both linalool and 1,8-cineole...?The combination of compounds is more desirable because the insecticidal spectrum of some binary mixtures is increased."

Singh, Rajwinder, Opender Koul, Pushpinder Rup, and Jawala Jindal. "Toxicity of some essential oil constituents and their binary mixtures against Chilo pattellas (Lepidoptera: Pyralidae)." International Journal of Tropical Insect Science 29.2 (2009): 93-101.

"Limonene exhibited synergistic interaction with citral, caryophyllene oxide and Benznidazole (decreasing by 17 times its IC50) and was the most effective and selective treatment."

[Moreno, érika, Sandra Leal, Elena Stashenko, and Liliana García. "Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)." BMC Complementary and Alternative Medicine 18.1 (2018): 1-16.]

"None of the other compounds were toxic to adults, but caryophyllene oxide and sesamin exhibited moderate larvicidal effects (LD50?>?150 μg/ml). A mixture of the four compounds in the same ratio as in the hexane extract showed higher toxicity (LD50 34 ng/mg insect) towards adult insects than the pure compounds."

Moussavi, Nastaran, Karl Egil Malterud, Bertin Mikolo, Dag Dawes, Fabrice Chandre, Vincent Corbel, Daniel Massamba, Hans J. Overgaard, and Helle Wangensteen. "Identification of chemical constituents of Zanthoxylum heitzii stem bark and their insecticidal activity against the malaria mosquito Anopheles gambiae." Parasites & Vectors 8 (2015).

"The in vitro trypanocidal activity of a 1?:?4 mixture of lupenone and caryophyllene oxide confirmed a synergistic effect of the terpenoids against epimastigotes forms of T. cruzi "

[Polanco-Hernández, Glendy, Fabiola Escalante-Erosa, Karlina García-Sosa, María E. Rosado, Eugenia Guzmán-Marín, Karla Y. Acosta-Viana, Alberto Giménez-Turba, Efraín Salamanca, and Luis M. Pe?a-Rodríguez. "Synergistic Effect of Lupenone and Caryophyllene Oxide against Trypanosoma cruzi." Evidence-Based Complementary and Alternative Medicine 2013.2013 (2013).]

"Oils with high sesquiterpene concentrations received a low rating, meaning that they smelled badly. In contrast, oils with high monoterpene percentages (but a low alpha-humulene or caryophyllene oxide concentration) got a high rating. Surprisingly, a mixed oil from different strains received the best rating."?

[Vito Mediavilla and Simon Steinemann?Essential oil of Cannabis sativa L. strains?International Hemp Association?from: https://www.internationalhempassociation.org/jiha/jiha4208.html?Accessed April 10, 2019]

"Comparison of the deterrent activity of ‘full mixtures' with respective artificial blends missing individual constituents demonstrates that, for most oils, minor constituents in a mixture can be as important as major constituents with respect to the overall feeding deterrent effect.?The rold of any individual compound is mixture-specific and depends on the interaction between the constituents of the mixture."

[AKHTAR, YASMIN, EMMANUELLE PAGES, ALEX STEVENS, ROD BRADBURY, CLAUDIO A. G. da CAMARA, and MURRAY B. ISMAN. "Effect of chemical complexity of essential oils on feeding deterrence in larvae of the cabbage looper." Physiological Entomology 37.1 (2012): 81-91.]

"Natural thyme oil showed greater toxicity than any single constituent or blend of constituents.??The toxicity of blends of selected constituents indicated a synergistic effect among the putatively active and inactive constituents, with the presence of all constituents necessary to reach the highest toxicity."

[Wu, Lipeng et al. “Acaricidal Activity and Synergistic Effect of Thyme Oil Constituents against Carmine Spider Mite (Tetranychus Cinnabarinus (Boisduval)).” Molecules (Basel, Switzerland) vol. 22,11 1873. 1 Nov. 2017, doi:10.3390/molecules22111873]

"However, the observed activity might be due to synergism between compounds present in the plant extract. The synergism among these compounds which contribute to the cytotoxic activity, is not only dependent on the concentration of the compounds, but also on the structure and interaction(s) between the compounds [27]. This can explain the differences in the cytotoxic effect between crude extracts and isolated compounds against the same cell lines, as shown in our earlier report"

[Malek, Sri Nurestri Abdul et al. “Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves.” Molecules (Basel, Switzerland) vol. 14,5 1713-24. 6 May. 2009, doi:10.3390/molecules14051713]

"The effectiveness of a binary 1:2 mixture of thymol and vanillin (0.05:0.1 microl per cm2) was found to be significantly more effective than thymol alone for a period of 120 min."

[Park YU, Koo HN, Kim GH.?Chemical composition, larvicidal action, and adult repellency of Thymus magnus against Aedes albopictus.?J Am Mosq Control Assoc. 2012 Sep;28(3):192-8.]

"Although none of these was active when presented individually at the levels present in the entrainment sample...the six-component blend and a blend of acetophenone, (Z)-3-hexenyl acetate, and 3-carene, in the same ratio and concentration as in a natural sample, was as attractive to female S. mosellana as the whole air entrainment sample."

[Birkett, Michael, Toby Bruce, Janet Martin, Lesley Smart, Jon Oakley, and Lester Wadhams. "Responses of Female Orange Wheat Blossom Midge, Sitodiplosis mosellana, to Wheat Panicle Volatiles." Journal of Chemical Ecology 30.7 (2004): 1319-1328.]

"The slow onset of inhibition of butyrylcholinesterase was also shown by individual constituents, such as 3-carene and beta-pinene. Analyses of the chemical composition of the oils and anti-butyrylcholinesterase activity of their constituents revealed that none of the compounds tested would account for the total activity of the oils and that synergy is likely."

[Savelev, Sergey U., Edward J. Okello, and Elaine K. Perry. "Butyryl- and acetyl-cholinesterase inhibitory activities in essential oils of Salvia species and their constituents." Phytotherapy Research 18.4 (2004): 315-324.]

"Furthermore, the combination of borneol and menthol significantly enhanced the permeation rate in the same concentration, compared with their effects when used alone.?Consequently, menthol combined with borneol can highly enhance fluconazole permeation through the ex vivo cornea."

[Liu, Jingjing, Shaoying Fu, Nan Wei, Yongsheng Hou, Xiaoning Zhang, and Hao Cui. "The effects of combined menthol and borneol on fluconazole permeation through the cornea ex vivo." European Journal of Pharmacology 688.1 (2012): 1-5.]

"These results demonstrated the synergic effects between TMPP (tetramethylpyrazine phosphate) and BO (borneol) for treating ischemia-reperfusion injury in the cortex and hippocampus regions."?

Yu, Bin, Ming Ruan, Tao Liang, Shi-Wen Huang, Yun Yu, Hai-Bo Cheng, and Xiang-Chun Shen. "The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy." Journal of Molecular Neuroscience 63.1 (2017): 70-83

"These results suggested that the blend provided more useful information for female wasps than the individual compounds. ...the blend attracted the wasps at all of the tested concentrations, while the response windows for each pure compound were narrow.?Additionally, at the 0.01 ng level, none of the individual compounds attracted A. ervi, while their mixtures attracted at a ten times lower level..."

[Takemoto, Hiroyuki, and Junji Takabayashi. "Parasitic Wasps Aphidius ervi are More Attracted to a Blend of Host-Induced Plant Volatiles than to the Independent Compounds." Journal of Chemical Ecology 41.9 (2015): 801-807.]

"Radical scavenging activity of Carum oil was than that of Ferula oil.?These differential activities between essential oils could be reflected to the main components and strong synergism between them."

[Kavoosi, Gholamreza, Asad Tafsiry, Ali Asghar Ebdam, and Vahid Rowshan. "Evaluation of Antioxidant and Antimicrobial Activities of Essential Oils from Carum copticum Seed and Ferula assafoetida Latex." Journal of Food Science 78.2 (2013): T356-T361.]??

"Our third case of study, the mixture of (R)-pulegone and citronellal, showed quite different results from those predicted by MM (Table ?(Table6),6), with observed LC50 values being markedly lower than expected. Moreover, CI [combination index] values were quite far below one, suggesting a real synergism between these two terpenes, which was supported also by the isobolograms..."

[Esteban Scalerandi, Guillermo A. Flores, Marcela Palacio, Maria Teresa Defagó, María Cecilia Carpinella, Graciela Valladares, Alberto Bertoni, and Sara María Palacios.?Understanding Synergistic Toxicity of Terpenes as Insecticides: Contribution of Metabolic Detoxification in Musca domestica. Front Plant Sci. 2018; 9: 1579.]

"...Terpinen-4-ol and c-terpinene exhibited a signi?cant insecticidal activityagainst both insects, but c-terpinene was more toxic than terpinen-4-ol. When tested in a binary mixture with the synthetic insecticides profenofos and methomyl, it was found that both compounds enhanced the insecticidal activity of these insecticides by two- to threefold. These results show that terpinen-4-ol and c-terpinene have a synergistic effect on the insecticidal activities of synthetic insecticides profenofos and methomyl."

[Mostafa A. Abbassy, Samir A. M. Abdelgaleil, & Rasha Y. A. Rabie.?Insecticidal and synergistic effects of Majoranahortensis essential oil and some of its majorconstituents.?Entomologia Experimentalis et Applicata 131(3):225 - 232 · May 2009]

"Otherwise, sabinene and terpinen-4-ol were strongly repellent against T. castaneum as well as the essential oil, while c-terpinene exhibited weaker repellency against T. castaneum compared with the positive control, DEET (N, N-diethyl-3-methylbenzamide). Moreover, only the essential oil exhibited strong repellency against L. serricorne, the three compounds exhibited weaker repellency against L. serricorne relative to DEET."

[Y. WANG, C. X. YOU, K. YANG, Y. WU, R. CHEN, W. J. ZHANG, Z. L. LIU, S. S. DU, Z. W. DENG, Z. F. GENG, AND J. HAN6.?Bioactivity of Essential Oil of Zingiber purpureum Rhizomes and Its Main Compounds against Two Stored Product Insects?Journal of Economic Entomology; Lanham Vol. 108, Iss. 3,?(Jun 2015): 925-932.]

"Our results showed imidacloprid treatment alone can significantly decrease aphid populations, and that combining insecticide with E?f (farnesene) further reduced numbers of apterous aphids...Our results demonstrate that imidacloprid can be effective in reducing the abundance of aphids in Chinese cabbage fields, but the degree of control can be even stronger in the presence of E?f."

[Liang-LiangCui, Jie Dong, Frédéric Francis, Ying-Jie Liu, Stéphanie Heuskin, Georges Lognay, Ju-Lian Chen, Claude Bragard, John F.Tooker, Yong Liua.?E-?-farnesene synergizes the influence of an insecticide to improve control of cabbage aphids in China.?Crop Protection Volume 35, May 2012, Pages 91-96]

"The essential oil fraction ofP. graveolens and its main components, geraniol and citronellol, exhibited additive effects with amphotericin B and with ketoconazole against both Aspergillus species.?The FIC index calculated from these results was 0.562, which indicates the strong additive effects of geraniol and amphotericin B."

[Shin, Seungwon. "Anti- Aspergillus activities of plant essential oils and their combination effects with ketoconazole or amphotericin b." Archives of Pharmacal Research 26.5 (2003): 389-393.]

"With sorbitol, geraniol MIC was increased by 64-fold and citronellol by 32-fold. The drugs caused leakage of intracellular material and inhibited ergosterol biosynthesis."

[Pereira Fde O, Mendes JM, Lima IO, Mota KS, Oliveira WA, Lima Ede O.?Antifungal activity of geraniol and citronellol, two monoterpenes alcohols, against Trichophyton rubrum involves inhibition of ergosterol biosynthesis.?Pharm Biol. 2015 Feb;53(2):228-34.]

"Overall, the present investigation revealed that the major components of P. roseum and specially the whole essential oil could be helpful in developing novel and safe mosquito control tools and also offer an environmentally safe and cheap tool for reducing Cx. pipiens mosquito populations."

[Tabari MA, Youssefi MR, Esfandiari A, Benelli G.?Toxicity of ?-citronellol, geraniol and linalool from Pelargonium roseum essential oil against the West Nile and filariasis vector Culex pipiens (Diptera: Culicidae).?Res Vet Sci. 2017 Oct;114:36-40.]

"Toxicity of these four major constituents in the same proportion as the natural oil, was greater than whole oil and each individual component. Removal of any four constituents produced a decreased in effectiveness."

[Gallardo A, Picollo MI, González-Audino P, Mougabure-Cueto G.?Insecticidal activity of individual and mixed monoterpenoids of geranium essential oil against Pediculus humanus capitis (Phthiraptera: Pediculidae).?J Med Entomol. 2012 Mar;49(2):332-5.]

"A strong synergism of DOX (doxorubicin) with NER (nerolidol) was found in the A2780 cells, while DOX acted synergistically with HUM (humulene) and CAO (b-caryophyllene) in the SKOV3 (ovarian cancer) cells. In the CCRF/CEM cells, a synergism of DOX with CAO and NER was observed."?

[Ambro?, Martin et al. “The Effects of Selected Sesquiterpenes from Myrica rubra Essential Oil on the Efficacy of Doxorubicin in Sensitive and Resistant Cancer Cell Lines.” Molecules (Basel, Switzerland) vol. 22,6 1021. 20 Jun. 2017, doi:10.3390/molecules22061021]

"CAO, NER and VAL synergistically potentiated the efficacy of DOX in cancer cell killing." >>>>Refers to Caryophyllene Oxide, Nerolidol, and Valencene<<<<

[Ambro?, Martin et al. “The Influence of Sesquiterpenes from Myrica rubra on the Antiproliferative and Pro-Oxidative Effects of Doxorubicin and Its Accumulation in Cancer Cells.” Molecules (Basel, Switzerland) vol. 20,8 15343-58. 21 Aug. 2015, doi:10.3390/molecules200815343]

"The presence of all constituents together in the artificial mixture caused a significant decrease in the number of eggs laid by females, at 0.26 mg liter(-1) (11 eggs), compared with the control (50 eggs). The toxicity of blends of selected constituents indicated that the presence of all constituents was necessary to reproduce the toxicity level of the natural oil."

[Attia, S., K. L. Grissa, G. Lognay, S. Heuskin, A. C. Mailleux, and T. Hance. "Chemical Composition and Acaricidal Properties of Deverra scoparia Essential Oil (Araliales: Apiaceae) and Blends of Its Major Constituents Against Tetranychus urticae (Acari: Tetranychidae)." Journal of Economic Entomology 104.4 (2011): 1220-1228.]

"Indian cassia was non-toxic alone, but the mixture of India cassia + green cardamom showed toxicity, clearly demonstrating a synergistic effect."?

Tripathi, Aran, Anil Singh, and Shikha Upadhyay. "Contact and fumigant toxicity of some common spices against the storage insects Callosobruchus maculatus (Coleoptera: Bruchidae) and Tribolium castaneum (Coleoptera: Tenebrionidae)." International Journal of Tropical Insect Science 29.3 (2009): 151-157.

"This study indicated that the combination of LM (l-menthol) and reboxetine, as well as LM and FLU (fluoxetine) showed synergistic effects."

Wang, Weidong, Yuanyuan Jiang, Enbo Cai, Bingchen Li, Yan Zhao, Hongyan Zhu, Lianxue Zhang, and Yugang Gao. "L-menthol exhibits antidepressive-like effects mediated by the modification of 5-HTergic, GABAergic and DAergic systems." Cognitive Neurodynamics 13.2 (2018): 191-200.

"Our results indicate that two of the three geranium oil constituents tested exhibit excellent anti-Candida activity and significant synergistic activity with fluconazole."

[Zore GB, Thakre AD, Rathod V, Karuppayil SM.?Evaluation of anti-Candida potential of geranium oil constituents against clinical isolates of Candida albicans differentially sensitive to fluconazole: inhibition of growth, dimorphism and sensitization.?Mycoses. 2011 Jul;54(4):e99-109.]

"Our results indicated that EO's induced a selective antimicrobial activity. A synergistic effect of EO's and tetracycline (TET) was noticed with a reduction rate ranged from 2 to 8-fold (of bacteria)."

[Miladi, Hanene, Tarek Zmantar, Bochra Kouidhi, Yasir Mohammed A Al Qurashi, Amina Bakhrouf, Yassine Chaabouni, Kacem Mahdouani, and Kamel Chaieb. "Synergistic effect of eugenol, carvacrol, thymol, p-cymene and ?-terpinene on inhibition of drug resistance and biofilm formation of oral bacteria.." Microbial pathogenesis 112 (2018): 156-163.]

"When thymol and cymene were applied simultaneously, it resulted in a greater antibacterial effect than when the compounds were applied separately."

[Bego?a Delgado, Alfredo Palop, Pablo S. Fernández & Paula M. Periago.?Combined effect of thymol and cymene to control the growth of Bacillus cereus vegetative cells?European Food Research and Technology volume 218, pages188–193(2004)]?

"This study indicates a synergistic interaction between essential oils and PBO (piperonyl butoxide) in inhibiting the cytochrome P450 and GST detoxification enzymes in Ae. aegypti."

[Waliwitiya R, Nicholson RA, Kennedy CJ, Lowenberger CA.?The synergistic effects of insecticidal essential oils and piperonyl butoxide on biotransformational enzyme activities in Aedes aegypti (Diptera: Culicidae).?J Med Entomol. 2012 May;49(3):614-23.]

"Data also suggest that ?-Elemene shows the synergistic effect when treated with hyperbaric oxygen in TBI (traumatic brain injury)..."

[Xiangen Meng, Na Li, Yu Zhang, Danfeng Fan, Chen Yang, Hang Li, Dazhi Guo, and Shuyi Pan.?Beneficial Effect of ?-Elemene Alone and in Combination with Hyperbaric Oxygen in Traumatic Brain Injury by Inflammatory Pathway?Translational Neuroscience 2018; 9: 33-37]

"The combination of ascorbic acid and rutin had higher antioxidant properties compared to the activity of the single compound alone, and showed a stronger effect against UV-induced reactive oxygen species generation."

[Gegotek, Agnieszka, Ewa Ambrozewicz, Anna Jastrzab, Iwona Jarocka-Karpowicz, and Elzbieta Skrzydlewska. "Rutin and ascorbic acid cooperation in antioxidant and antiapoptotic effect on human skin keratinocytes and fibroblasts exposed to UVA and UVB radiation." Archives of Dermatological Research 311.3 (2019): 203-219.]

"Subcutaneous and orthotopic xenograft studies also showed that tumor volumes were significantly lower in mice receiving combined TMZ/Rutin treatment as compared to TMZ or rutin alone treatment. Moreover, immunoblotting analysis showed that TMZ activated JNK activity to induce protective response autophagy, which was blocked by rutin, resulting in decreased autophagy and increased apoptosis, suggesting that rutin enhances TMZ efficacy both in vitro and in vivo..."

[Zhang, P., Sun, S., Li, N. et al. Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition. J Neurooncol 132, 393–400 (2017).]

"Compared with Quercetin and Rutin, FPL (an extract of persimmon leaves where these two compounds are the primary constituents) showed higher cytotoxicity at 12.5 and 25 μg/ml concentrations and also presented lower IC50 in PC-3 cells."

[Ding, Yan, Kai Ren, Huanhuan Dong, Fei Song, Jing Chen, Youtian Guo, Yanshan Liu, Weijie Tao, and Yali Zhang. "Flavonoids from persimmon (Diospyros kaki L.) leaves inhibit proliferation and induce apoptosis in PC-3 cells by activation of oxidative stress and mitochondrial apoptosis." Chemico-Biological Interactions 275 (2017): 210-217]

"Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug."

[Lefort, émilie, and Jonathan Blay. "The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells." Clinical & Experimental Metastasis 28.4 (2011): 337-349.]

"Apoptosis assay revealed that TRAIL or apigenin alone induced a marked apoptosis in RAFLS and their combination yielded a synergistic increase in RAFLS apoptosis."

[Sun, Q., Jiang, S., Yang, K. et al. Apigenin enhances the cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes. Mol Biol Rep 39, 5529–5535 (2012)]

"When quercetin was combined with quercitrin, enhancement of anti-DENV-2 activity and reduced cytotoxicity were observed. However, the synergistic efficacy of the flavonoid combination was still less than that of the EA fraction."

[Chiow, K.H., M.C. Phoon, Thomas Putti, Benny K.H. Tan, and Vincent T. Chow. "Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection." Asian Pacific Journal of Tropical Medicine 9.1 (2015): 1-7.]

"The combination of cisplatin with quercetin synergistically inhibits cell growth and triggers apoptosis in HepG2 cells. Our data revealed that the combination of quercetin and cisplatin was significantly (P?<?0.05) effective in inducing growth suppression and apoptosis in HepG2 cells, when compared with single agent treatment."

[Zhao, Ji-ling, Jing Zhao, and Hong-jun Jiao. "Synergistic Growth-Suppressive Effects of Quercetin and Cisplatin on HepG2 Human Hepatocellular Carcinoma Cells." Applied Biochemistry and Biotechnology 172.2 (2013): 784-791.]?

"The experiment results suggest that quercetin can increase chemosensitivity of DDP and VC on the two cell lines (A549 human lung adenocarcinoma)."

[Zhan, Xuejun, Runxiang Zhang, Yanping Xu, Shuhua Yang, Daze Xie, and Liwei Tan. "Empirical studies about quercetin increasing chemosensitivity on human lung adenocarcinoma cell line A549." The Chinese-German Journal of Clinical Oncology 11.7 (2012): 380-383.]

"We found that Quercetin synergistically enhanced rituximab-induced growth inhibition and apoptosis in DLBCL cell lines."

[Li, Xin, Xinhua Wang, Mingzhi Zhang, Aimin Li, Zhenchang Sun, and Qi Yu. "Quercetin Potentiates the Antitumor Activity of Rituximab in Diffuse Large B-Cell Lymphoma by Inhibiting STAT3 Pathway." Cell Biochemistry and Biophysics 70.2 (2014): 1357-1362.]?

"Co-administration of luteolin and paclitaxel resulted in an increase in apoptosis compared with the treatment of paclitaxel alone..., immunoblotting analysis also showed that the co-administration of luteolin and paclitaxel activated caspase-8 and caspase-3 and increased the expression of Fas."

[Yang, Mon-Yuan, Chau-Jong Wang, Nai-Fang Chen, Wen-Hsin Ho, Fung-Jou Lu, and Tsui-Hwa Tseng. "Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3.." Chemico-biological interactions 213 (2014): 60-68.]

"...combined administration of luteolin and 5-FU in Solid Ehrlich Carcinoma model increased levels of p53, p21, caspase 3, DRAM and survivability...current results proved the antitumor therapeutic effects of luteolin alone or combined with 5-FU as a novel strategy for cancer therapy."

[Soliman, Nema A, Rania N Abd-Ellatif, Amira A ELSaadany, Shahinaz M Shalaby, and Asmaa E Bedeer. "Luteolin and 5-flurouracil act synergistically to induce cellular weapons in experimentally induced Solid Ehrlich Carcinoma: Realistic role of P53; a guardian fights in a cellular battle.." Chemico-biological interactions 310 (2019): 108740-108740.]

"In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone."

[Jeon, Ye, Young Ahn, Won Chung, Hyun Choi, and Young Suh. "Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells." Tumor Biology 36.8 (2015): 6349-6359.]

"...a combinational treatment of cisplatin and luteolin induced more effectively cell growth inhibition, compared to cisplatin treatment alone."

[Wu, Bin, Qiang Zhang, Weiming Shen, and Jun Zhu. "Anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line." Molecular and Cellular Biochemistry 313.2 (2008): 125-132.]

"In the majority of cases, luteolin, when combined with IFN-?, had additive effects in modulating cell proliferation, IL-1?, TNF-a, MMP-9 and TIMP-1."

[Sternberg, Zohara, Kailash Chadha, Alicia Lieberman, Allison Drake, David Hojnacki, Bianca Weinstock-Guttman, and Frederick Munschauer. "Immunomodulatory responses of peripheral blood mononuclear cells from multiple sclerosis patients upon in vitro incubation with the flavonoid luteolin: additive effects of IFN-?." Journal of Neuroinflammation 6 (2009): 28-28.]

"luteolin enhanced anti-proliferation effect of cisplatin on cisplatin-resistant ovarian cancer CAOV3/DDP cells. Flow cytometry revealed that luteolin enhanced cell apoptosis in combination with cisplatin. Western blotting and qRT-PCR assay revealed that luteolin increased cisplatin-induced downregulation of Bcl-2 expression. In addition, wound-healing assay and Matrigel invasion assay showed that luteolin and cisplatin synergistically inhibited migration and invasion of CAOV3/DDP cells. Moreover, in vivo, luteolin enhanced cisplatin-induced reduction of tumor growth as well as induction of apoptosis."

[Wang, Haixia, Youjun Luo, Tiankui Qiao, Zhaoxia Wu, and Zhonghua Huang. "Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion." Journal of Ovarian Research 11.1 (2018): 1-12.]

"Vitexin can cooperate with HBO to sensitize the glioma radiotherapy...The present results showed that the combination of HBO and vitexin could synergistically sensitize the glioma radiotherapy."

[Xie, T., J.-R. Wang, C.-G. Dai, X.-A. Fu, J. Dong, and Q. Huang. "Vitexin, an inhibitor of hypoxia-inducible factor-1a, enhances the radiotherapy sensitization of hyperbaric oxygen on glioma." Clinical and Translational Oncology 22.7 (2020): 1086-1093.]

"Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point."

[Tsai, Ming-Shiun, Ying-Han Wang, Yan-Yun Lai, Hsi-Kai Tsou, Gan-Guang Liou, Jiunn-Liang Ko, and Sue-Hong Wang. "Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice.." Toxicology letters 290 (2018): 97-109.]

"After the combined application of both phenols, a synergistic effect of kaempferol plus low but not high doses of (-)-epicatechin was observed."

[Escandón, R.A., del Campo, M., López-Solis, R. et al. Antibacterial effect of kaempferol and (-)-epicatechin on Helicobacter pylori . Eur Food Res Technol 242, 1495–1502 (2016)]

"Of particular interest is that in combination, the two PACs [oridonin and wogonin] were synergistic in their cytotoxicity to five of six of the primary cultures and to both the cell lines..."

[Chen, Sophie, Matt Cooper, Matt Jones, Thumuluru Madhuri, Julie Wade, Ashleigh Bachelor, and Simon Butler-Manuel. "Combined activity of oridonin and wogonin in advanced-stage ovarian cancer cells." Cell Biology and Toxicology 27.2 (2010): 133-147.]

"Hence, wogonin significantly sensitized resistant HNC cells to cisplatin both in vitro and in vivo. Our study revealed that wogonin could act synergystically with cisplatin and thereby circumvent the resistance to cisplatin in HNC cells."

[Kim, Eun, Hyejin Jang, Daiha Shin, Seung Baek, and Jong-Lyel Roh. "Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer." Apoptosis 21.11 (2016): 1265-1278.]?

All of this is taken directly from The Big Book of Terps. Hit me up to get a copy of this 580 page hardcover textbook with nearly 1,300 citations.

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