1. Please check and comment entries here.
Table of Contents

    Topic review

    Peppers Ethnopharmacology

    View times: 17
    Submitted by: Roberto Parise-Filho

    Definition

    Piper, Capsicum, and Pimenta are the main genera of peppers consumed worldwide. The traditional use of peppers by either ancient civilizations or modern societies has raised interest in their biological applications, including cytotoxic and antiproliferative effects. 

    1. Introduction

    Antineoplastic chemotherapy remains a challenge nowadays since the current drugs affect both tumorigenic and healthy cells, causing undesirable adverse effects due to low selectivity and high toxicity [1]. Moreover, resistance against anticancer drugs may brutally impair the effectiveness of chemotherapy. These issues illustrate the need for new anticancer therapies and the development of more effective and safer antitumor agents [2].

    Natural products play an important role in the discovery of new drugs and in addition, they are an important source of innovative molecular scaffolds for the treatment of various diseases, especially cancer. According to Newman and Cragg (2016) [3], among antitumor drugs approved worldwide between 1940 and 2014, 49% of the new molecular entities were natural products or directly derived compounds. Big pharmaceutical companies have retreated from their natural product-derived drug discovery projects, yet several authors have reported new methods and techniques that enhance exploration of the chemical diversity of natural products (e.g., mass spectrometry, genomics, proteomics, automated extract production, and phenotypic high-throughput screening) [3][4][5][6][7][8]. Of note is that these new techniques have allowed the identification of many active compounds in traditional medicines [9][10][11][12][13][14][15].

    Primarily used as spices for foods due to the pungent flavor and aroma, peppers have an important position as excellent producers of secondary metabolites that have a wide range of pharmacological properties. For instance, the Piper, Capsicum, and Pimenta genera have been used by ancient civilizations (e.g., Chinese, Mayan, and Caribbean traditional medicines) in formulations for cancer treatment. However, their value as a natural source for cytotoxic compounds has only gained attention in the last decades [16][17][18][19].

    2. Pepper Ethnopharmacology

    Piperaceae, a promising natural source for new drugs, is a pantropical family of plants comprising approximately 4000 species that contain biologically active natural products, including amides, lignans, neolignans, benzopyrene, pyrones, flavonoids, and terpenoids. These compounds led peppers to be broadly used in folk medicine worldwide, especially in Asia and Latin America [16][20][21]. The Piperaceae family has five genera: Macropiper, Zippelia, Peperomia, Manekia, and Piper, which is the largest genus of this family (nearly 2000 species) [22]. Many Piper species are popularly used for the treatment of several disorders, such as rheumatism [23], cardiac arrhythmias [24], asthma [25], upset stomach [26], and many kinds of infections [21]. Further biological properties have been reported for secondary metabolites of Piper, such as antinociceptive [27], anti-inflammatory [28][29], antiplatelet aggregation [30], antioxidant [31], antiophidic [32], anxiolytic/antidepressant [33], antidiabetic [32], hepatoprotective [34], leishmanicidal [35], anti-secretory [36], and cytotoxic effects [37].

    The Solanaceae family comprises 98 genera and nearly 2700 species [38]. Interestingly, common dietary ingredients appear in Solanaceae subfamilies, such as tomatoes and potatoes (Solanum), bell and chili peppers (Capsicum), and tobacco (Nicotiana) [39]. The biological aspects of this family are primarily related to their alkaloid content (e.g., tropanes, nicotine, capsaicinoids, and glycoalkaloids) [40][41][42][43][44][45]. Chili peppers that are found in the Capsicum genus are believed to have been part of the human diet since immemorial time. It is well established that Central and South American Indians grew these peppers before Christopher Columbus’ arrival [46]. The Capsicum genus comprises ~27 species with a large number of varieties [47][48]. Among the related biological activities, chili peppers are believed to act as antioxidants [49][50] and hypoglycemic [51], antimicrobial [12], anti-inflammatory [52], thermoregulatory [53], and antitumor [54] agents.

    According to several authors [55][56], the Myrtaceae family is composed of 5500 species that are clustered into 140 genera that are widely distributed in neotropical forests and savannas. This massive family is widely explored for the production of essential oils and spices (Myrtus sp. and Pimenta sp.) [57][58], in natura food [59], and wood-derived products (Eucalyptus sp.) [60]. The Pimenta genus comprises 16 species mainly found in the Caribbean region [55][61][62], and its essential oil and leaf extracts have several biological properties such as cytotoxicity [63], anti-nociceptive and anti-inflammatory [64][65], antioxidant [66][67], insecticidal [68], antimicrobial [69][70], and antifungal [71] effects.

    3. The Apoptosis Pathways

    Apoptosis, a programmed senescence process of cell death, naturally occurs (i) when cells lose their proliferative capacity after a certain number of cell divisions, (ii) in cellular defense events (e.g., immune reactions), and (iii) and after severe cellular damage (e.g., solar radiation) [72][73]. Nevertheless, apoptosis can be avoided due to deregulation of extrinsic and intrinsic key components that trigger its pathway, a very common characteristic in many cancers [74]. Advances in the understanding of these biochemical pathways have created opportunities to modulate defective processes through the proapoptotic activity induced by natural and synthetic compounds [75][76].

    Most known proapoptotic effects act as upregulation of death receptors, leading to activation of caspases and cell death (via extrinsic pathway) [77][78]. On the other hand, the intrinsic pathway can be triggered by compounds that generally produce high levels of damaged DNA [79]. These compounds, natural or synthetic, can also stimulate proapoptotic regulators of the B-cell lymphoma 2 (BCL-2) family [80], promoting the collapse of internal mitochondrial membrane potential (Δψ) followed by an overflow of the mitochondrial content, such as cytochrome c (Cyt c), direct IAP binding protein with low pI), and HtrA2 (High temperature requirement protein A2 (DIABLO) [81][82]. In the cytosol, Cyt c forms the apoptosome, which promotes the activation of caspases, resulting in apoptosis [83][84].

    Among the reviewed compounds, the secondary metabolites of peppers, some analogues, and their potency over cancer cell lines are described in Table 1. Moreover, as can be seen in the next items of this review, chemical constituents are described in detail and cell death mechanisms, when available, are also presented.

    Table 1. Potency (IC50; µM) of pepper-derived compounds against several cancer cell lines 1.

    Compound Cell Line and IC50 (µM) References
    Piperolactam A (1) A549 (10.1); HCT15 (27.8); SK-MEL-2 (18.3); SK-OV-3 (18.3) [85][86]
    Piperolactam B (2) A549 (21.7); HCT15 (21.3); SK-MEL-2 (11.6); SK-OV-3 (14.4); P-388 (46.1) [85][86]
    Piperolactam C (3) A549 (>162.0); P-388 (78.0); HT-29 (69.0) [85]
    4 L1210 (1.6) [87][88]
    5 L1210 (2.6) [87][88]
    6 L1210 (2.3) [87][88]
    7 L1210 (1.6) [87][88]
    8 L1210 (1.8) [87][88]
    9 MCF-7 (2.0) [89]
    Piplartine or Piperlongumine (10) 518A2 (2.6); A2780 (0.5); A549 (1.9); CEM (4.4); GBM10 (3.8); HCT116 (6.0); HCT8 (2.2); HL60 (5.3); HT1080 (3.4); HT-29 (1.4); JURKAT (5.3); K-562 (5.7); KB (5.6); MCF-7 (5.0); MOLT-4 (1.7); MRC-5 (35.0); SF188 (3.9); SKBR3 (4.0); T98G (4.9); WI38 (26.8); ZR-75-30 (5.9) [88][90][91][92][93][94]
    11 A549 (4.1); MCF-7 (4.2) [88]
    12 A549 (4.7); MCF-7 (4.9) [88]
    13 A549 (1.8); MCF-7 (1.6) [88]
    14 A549 (2.0); MCF-7 (1.8) [88]
    15 A549 (3.8); MCF-7 (5.0) [88]
    16 A549 (24.0); MDA-MB-231 (11.7) [93]
    17 A549 (18.0); MDA-MB-231 (23.7) [93]
    18 A549 (19.8); MDA-MB-231 (6.7) [93]
    19 A549 (3.9); MDA-MB-231 (6.1) [93]
    20 A549 (4.1); MDA-MB-231 (7.3) [93]
    21 A549 (4.8); MDA-MB-231 (2.7) [93]
    22 A549 (2.7); MDA-MB-231 (2.5) [93]
    23 A549 (2.2); MDA-MB-231 (2.1) [93]
    Pipermethystine 24 HepG2 (not reported) [95]
    Piperlonguminine 25 MCF-7 (6.0); MCF-12A (50.8); MDA-MB-231 (261.7); MDA-MB-468 (8.0); SW-620 (16.9) [96]
    Pellitorine 26 HL60 (58.0); MCF-7 (8.0) [97][98]
    Sarmetine 27 P-388 (ED50 = 13.0) [99]
    Piperine 28 A549 (427.5); COLO-205 (46.0); HeLa (95.0); Hep-G2 (70.0); IMR-32 (89.0); MCF-7 (99.0) [100][101][102]
    Piperninaline 29 L5178Y (17.0) [103]
    Dehydropiperninaline 30 L5178Y (8.9) [103]
    Aduncamide 31 KB (ED50 = 18.0) [104][105]
    32 Not active [106]
    33 Not active [106]
    34 Not active [106]
    Piperarborenine A 35 A549 (4.23); HT-29 (6.21); P-388 (0.21) [85]
    Piperarborenine B 36 A549 (1.39); HT-29 (2.41); P-388 (0.13) [85]
    Piperarborenine C 37 A549 (0.23); HT-29 (0.26); P-388 (0.18) [85]
    Piperarborenine D 38 A549 (0.28); HT-29 (0.35); P-388 (0.20) [85]
    Piperarborenine E 39 A549 (0.19); HT-29 (0.22); P-388 (0.02) [85]
    Piperarboresine 40 A549 (5.01); HT-29 (5.69); P-388 (4.87) [85]
    Piplartine-dimer A 41 P-388 (8.48) [85]
    Chabamide 42 A549 (67.3); CNE (67.0); COLO-205 (5.4); DU-145 (16.0); HeLa (24.0; 189.8); HepG2 (60.8); K-562 (10.8); MCF-7 (39.1); SGC-7901 (12.0) [107][108]
    Chabamide F 43 COLO-205 (181.7); HeLa (119.4); HepG2 (44.6); HT-29 (259.7); MCF-7 (49.9) [107]
    Chabamide G 44 COLO-205 (0.0369); HeLa (85.3); HepG2 (108.0); MCF-7 (51.4) [107]
    Chabamide H 45 COLO-205 (69.5); HepG2 (253.5); MCF-7 (319.4) [107]
    Chabamide I 46 COLO-205 (80.5); HeLa (263.4) [107]
    Chabamide J 47 HT-29 (450.4) [107]
    Chabamide K 48 COLO-205 (379.4); Hela (191.0); HepG2 (437.2); HT-29 (397.8) [107]
    cis-Yangonin 49 A2780 (2.9); K652 (1.6) [109]
    trans-Yangonin 50 A2780 (9.3); K652 (5.5) [109]
    Demethoxyyangonin 51 A2780 (16.6); K652 (12.6) [109]
    Kavain 52 A2780 (11.0); K652 (23.2) [109]
    Methysticin 53 A375 (65.0); HaCaT (29.0) [110]
    54 A375 (65.0); HaCaT (29.0) [110]
    Flavokavain A 55 MCF-7 (25.0); MDA-MB-231 (17.5) [111][112]
    Flavokavain B 56 A2058 (18.3); ACC-2 (4.7); CaCo-2 (9.9); Cal-27 (26.7); DU-145 (3.9); H460 (18.2); HaCaT (13.6); HCT116 (7.5); HuH7 (15.9); HSC-3 (17.2); LAPC4 (32.0); LNCaP (48.3); MCF-7 (38.4); MCF-7/HER2 (13.6); MDA-MB-231 (12.3/45.0); NCI-H727 (11.3); PC-3 (6.2); RL (8.2); SKBR3/HER2 (10.0); SK-LMS-1 (4.4) [112][113][114][115][116][117][118]
    Flavokavain C 57 A549 (40.3); CaSKi (39.9); CCD-18Co (160.9); EJ (8.3); HCT116 (12.7); HepG2 (60.0); HT-29 (39.0); L-02 (57.0); MCF-7 (47.6); RT-4 (1.5) [119][120]
    58 CaCo-2 (10.0); HaCaT (10.9); HCT116 (9.2); MCF-7 (10.5); NCI-H727 (11.0); PC-3 (9.6); RL (10.1) [112]
    59 CaCo-2 (11.2); HaCaT (10.4); HCT116 (7.7); HuH7 (15.0); MCF-7 (10.3); MDA-MB-231 (13.2); NCI-H727 (14.8); PC-3 (7.3); RL (9.0) [112]
    60 CaCo-2 (9.6); HaCaT (10.5); HCT116 (10.0); HuH7 (16.6); MCF-7 (15.9); NCI-H727 (9.9); PC-3 (8.7); RL (8.9) [112]
    61 CaCo-2 (9.2); HCT116 (12.4); MCF-7 (8.8); PC-3 (13.2); RL (5.4) [112]
    62 HCT116 (54.1); MCF-7 (7.3); [121]
    63 CaCo-2 (5.8); HaCaT (7.2); HCT116 (6.9); HuH7 (15.5); MCF-7 (9.4); MDA-MB-231 (12.9); NCI-H727 (11.4); PC-3 (5.1); RL (6.9) [112]
    64 CaCo-2 (3.9); HaCaT (5.3); HCT116 (4.3); HuH7 (8.9); MCF-7 (9.4); MDA-MB-231 (8.7); NCI-H727 (8.2); PC-3 (3.1); RL (5.9) [112]
    65 CaCo-2 (4.5); HaCaT (8.7); HCT116 (4.2); HuH7 (9.8); MCF-7 (8.9); MDA-MB-231 (13.0); NCI-H727 (4.0); PC-3 (8.1); RL (9.0) [112]
    66 CaCo-2 (8.8); HaCaT (7.7); HCT116 (6.8); HuH7 (14.1); MCF-7 (9.3); MDA-MB-231 (9.9); NCI-H727 (8.7); PC-3 (7.6); RL (8.3) [112]
    67 CaCo-2 (5.5); HaCaT (7.6); HCT116 (6.2); HuH7 (14.6); MCF-7 (7.7); MDA-MB-231 (10.7); NCI-H727 (5.5); PC-3 (5.5); RL (6.4) [112]
    68 CaCo-2 (5.7); HaCaT (7.6); HCT116 (5.4); HuH7 (12.7); MCF-7 (7.5); MDA-MB-231 (8.2); NCI-H727 (6.0); PC-3 (5.8); RL (6.5) [112]
    69 CaCo-2 (6.8); HaCaT (9.0); HCT116 (6.2); HuH7 (13.9); MCF-7 (9.5); MDA-MB-231 (11.1); NCI-H727 (11.3); PC-3 (7.1); RL (8.3) [112]
    70 CaCo-2 (2.6); HaCaT (2.8); HCT116 (2.7); HuH7 (4.9); MCF-7 (5.0); MDA-MB-231 (3.3); NCI-H727 (4.1); PC-3 (2.5); RL (3.4) [112]
    Grandisin 71 EAT (0.2); HL60 (60.0); U937 (30.0); V79 (174.0) [122][123]
    72 A549 (6.90); SK-MEL-2 (4.50); SK-OV-3 (9.40) [86]
    73 3T3-A31 (0.043) [124]
    Conocarpan 74 A549 (11.2); HL60 (5.8); MCF-7 (7.8); SMMC-7721 (8.9); SW-480 (2.1) [125]
    Decurrenal 75 MCF-7 (169.1) [126]
    Eupomatenoid-5 76 786-0 (TGI = 6.6); HT-29 (TGI = 48.5); K-562 (TGI = 338.5); MCF-7 (TGI = 21.2); NCI-H460 (TGI = 34.8); OVCAR-3 (TGI = 18.7); PC-3 (TGI = 21.0); UACC-62 (TGI = 27.9) [127]
    Capsaicin 77 3T3 (83.0); A375 (6.0); A2058 (200.0); AsPC1 (150.0); B16F10 (117.0); BxPC3 (150.0); HepG2 (50.0); MCF-7 (53.0); MCF-10A H-ras (56.0); MDA-MB-231 (21.7); PC-3 (20.0); RT-4 (80.0) [128][129][130]
    78 B16F10 (87.0); MCF-7 (32.0) [128][129][130]
    79 B16F10 (38.0); MCF-7 (28.0); MDA-MB-231 (87.0) [131]
    80 B16F10 (75.0); MDA-MB-231 (109.0) [132]
    81 B16F10 (50.0); MCF-7 (32.0); MDA-MB-231 (14.2) [129]
    82 B16F10 (120.0); MDA-MB-231 (75.0) [132]
    83 MCF-7 (142.4); MDA-MB-231 (104.6) [133]
    84 MCF-7 (144.6); MDA-MB-231 (173.2) [133]
    85 B16F10 (130.0); SK-MEL-28 (85.0) [130]
    86 A2058 (55.2); SK-MEL-25 (67.2); U-87 (86.9) [134]
    Capsanthin 87 DU-145 (ND); PC-3 (ND) [135][136]
    Capsorubin 88 A549 (< 20.0) [135][136]
    Ericifolin 89 LNCaP (< 5.0) [137]
    Nilocitin 90 HCT116 (19.4); HepG2 (22.8); MCF-7 (40.8) [63]
    Pedunculagin 91 HCT116 (4.4); HepG2 (6.4); MCF-7 (18.4) [63]
    Castalagin 92 HCT116 (7.4); HepG2 (9.8); MCF-7 (26.2) [63]
    Grandinin 93 HCT116 (13.8); HepG2 (18.4); MCF-7 (22.1) [63]

    1 IC50 = half of maximal inhibitory concentration; ED50 = median of effective dose; TGI = total growth inhibition; ND = not determined.

    The entry is from 10.3390/molecules26061521

    References

    1. Pedersen, B.; Koktved, D.P.; Nielsen, L.L. Living with Side Effects from Cancer Treatment-A Challenge to Target Information. Scand. J. Caring Sci. 2013, 27, 715–723.
    2. He, Q.; Shi, J. MSN Anti-Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition. Adv. Mater. 2014, 26, 391–411.
    3. Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629–661.
    4. Koehn, F.E.; Carter, G.T. The Evolving Role of Natural Products in Drug Discovery. Nat. Rev. Drug Discov. 2005, 4, 206–220.
    5. Harvey, A.L.; Edrada-Ebel, R.; Quinn, R.J. The Re-Emergence of Natural Products for Drug Discovery in the Genomics Era. Nat. Rev. Drug Discov. 2015, 14, 111–129.
    6. Yao, H.; Liu, J.; Xu, S.; Zhu, Z.; Xu, J. The Structural Modification of Natural Products for Novel Drug Discovery. Expert Opin. Drug Discov. 2017, 12, 121–140.
    7. Zhang, M.M.; Qiao, Y.; Ang, E.L.; Zhao, H. Using Natural Products for Drug Discovery: The Impact of the Genomics Era. Expert Opin. Drug Discov. 2017, 12, 475–487.
    8. Zhang, A.; Sun, H.; Wang, X. Mass Spectrometry-Driven Drug Discovery for Development of Herbal Medicine. Mass Spectrom. Rev. 2018, 37, 307–320.
    9. Chaveerach, A.; Mokkamul, P.; Sudmoon, R.; Tanee, T. Ethnobotany of the Genus Piper (Piperaceae) in Thailand. Ethnobot. Res. Appl. 2006, 4, 223–231.
    10. Meghvansi, M.K.; Siddiqui, S.; Khan, M.H.; Gupta, V.K.; Vairale, M.G.; Gogoi, H.K.; Singh, L. Naga Chilli: A Potential Source of Capsaicinoids with Broad-Spectrum Ethnopharmacological Applications. J. Ethnopharmacol. 2010, 132, 1–14.
    11. Khan, F.A.; Mahmood, T.; Ali, M.; Saeed, A.; Maalik, A. Pharmacological Importance of an Ethnobotanical Plant: Capsicum Annuum L. Nat. Prod. Res. 2014, 28, 1267–1274.
    12. Cichewicz, R.H.; Thorpe, P.A. The Antimicrobial Properties of Chile Peppers (Capsicum Species) and Their Uses in Mayan Medicine. J. Ethnopharmacol. 1996, 52, 61–70.
    13. Corson, T.W.; Crews, C.M. Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials. Cell 2007, 130, 769–774.
    14. Srinivas, C.; Sai Pavan Kumar, C.N.S.; China Raju, B.; Jayathirtha Rao, V.; Naidu, V.G.M.; Ramakrishna, S.; Diwan, P. V First Stereoselective Total Synthesis and Anticancer Activity of New Amide Alkaloids of Roots of Pepper. Bioorg. Med. Chem. Lett. 2009, 19, 5915–5918.
    15. Shamaladevi, N.; Lyn, D.A.; Shaaban, K.A.; Zhang, L.; Villate, S.; Rohr, J.; Lokeshwar, B.L. Ericifolin: A Novel Antitumor Compound from Allspice That Silences Androgen Receptor in Prostate Cancer. Carcinogenesis 2013, 34, 1822–1832.
    16. Wang, Y.-H.; Morris-Natschke, S.L.; Yang, J.; Niu, H.-M.; Long, C.-L.; Lee, K.-H. Anticancer Principles from Medicinal Piper ( Hú Jiāo) Plants. J. Tradit. Complement. Med. 2014, 4, 8–16.
    17. Aggarwal, B.B.; Ichikawa, H.; Garodia, P.; Weerasinghe, P.; Sethi, G.; Bhatt, I.D.; Pandey, M.K.; Shishodia, S.; Nair, M.G. From Traditional Ayurvedic Medicine to Modern Medicine: Identification of Therapeutic Targets for Suppression of Inflammation and Cancer. Expert Opin. Ther. Targets 2006, 10, 87–118.
    18. Caamal-Fuentes, E.; Torres-Tapia, L.W.; Simá-Polanco, P.; Peraza-Sánchez, S.R.; Moo-Puc, R. Screening of Plants Used in Mayan Traditional Medicine to Treat Cancer-like Symptoms. J. Ethnopharmacol. 2011, 135, 719–724.
    19. Zhang, L.; Lokeshwar, B.L. Medicinal Properties of the Jamaican Pepper Plant Pimenta Dioica and Allspice. Curr. Drug Targets 2012, 13, 1900–1906.
    20. López, S.N.; Lopes, A.A.; Batista, J.M.; Flausino, O.; Bolzani, V.D.S.; Kato, M.J.; Furlan, M. Geranylation of Benzoic Acid Derivatives by Enzymatic Extracts from Piper Crassinervium (Piperaceae). Bioresour. Technol. 2010, 101, 4251–4260.
    21. Nascimento, J.C.d.; Paula, d.V.F.; David, J.M.; David, J.P. Occurrence, Biological Activities and 13C NMR Data of Amides from Piper (Piperaceae). Química Nova 2012, 35, 2288–2311.
    22. Quijano-Abril, A.; Callejas-Posada, R.; Miranda-Esquivel, D.R. Areas of Endemism and Distribution Patterns for Neotropical Piper Species (Piperaceae). J. Biogeogr. 2006, 33, 1266–1278.
    23. Yarnell, E. Herbs for Rheumatoid Arthritis. Altern. Complement. Ther. 2017, 23, 149–156.
    24. Srinivasan, K. Biological Activities of Red Pepper ( Capsicum Annuum ) and Its Pungent Principle Capsaicin: A Review. Crit. Rev. Food Sci. Nutr. 2016, 56, 1488–1500.
    25. Kim, S.-H.; Lee, Y.-C. Piperine Inhibits Eosinophil Infiltration and Airway Hyperresponsiveness by Suppressing T Cell Activity and Th2 Cytokine Production in the Ovalbumin-Induced Asthma Model. J. Pharm. Pharmacol. 2009, 61, 353–359.
    26. Mehmood, M.H.; Gilani, A.H. Pharmacological Basis for the Medicinal Use of Black Pepper and Piperine in Gastrointestinal Disorders. J. Med. Food 2010, 13, 1086–1096.
    27. López, K.S.E.; Marques, A.M.; Moreira, D.D.L.; Velozo, L.S.; Sudo, R.T.; Zapata-Sudo, G.; Guimarães, E.F.; Kaplan, M.A.C. Local Anesthetic Activity from Extracts, Fractions and Pure Compounds from the Roots of Ottonia Anisum Spreng. (Piperaceae). Ann. Braz. Acad. Sci. 2016, 88, 2229–2237.
    28. Fusco, B.M.; Giacovazzo, M. Peppers and Pain. The Promise of Capsaicin. Drugs 1997, 53, 909–914.
    29. Parise-Filho, R.; Pastrello, M.; Pereira Camerlingo, C.E.; Silva, G.J.; Agostinho, L.A.; de Souza, T.; Motter Magri, F.M.; Ribeiro, R.R.; Brandt, C.A.; Polli, M.C. The Anti-Inflammatory Activity of Dillapiole and Some Semisynthetic Analogues. Pharm. Biol. 2011, 49, 1173–1179.
    30. Park, B.S.; Son, D.J.; Park, Y.H.; Kim, T.W.; Lee, S.E. Antiplatelet Effects of Acidamides Isolated from the Fruits of Piper Longum L. Phytomedicine 2007, 14, 853–855.
    31. Amarowicz, R. Antioxidant Activity of Peppers. Eur. J. Lipid Sci. Technol. 2014, 116, 237–239.
    32. Bezerra, D.P.; Pessoa, C.; de Moraes, M.O.; Saker-Neto, N.; Silveira, E.R.; Costa-Lotufo, L. V Overview of the Therapeutic Potential of Piplartine (Piperlongumine). Eur. J. Pharm. Sci. 2013, 48, 453–463.
    33. Cícero Bezerra Felipe, F.; Trajano Sousa Filho, J.; de Oliveira Souza, L.E.; Alexandre Silveira, J.; Esdras de Andrade Uchoa, D.; Rocha Silveira, E.; Deusdênia Loiola Pessoa, O.; de Barros Viana, G.S. Piplartine, an Amide Alkaloid from Piper Tuberculatum, Presents Anxiolytic and Antidepressant Effects in Mice. Phytomedicine 2007, 14, 605–612.
    34. Koul, I.; Kapil, A. Evaluation of the Liver Protective Potential of Piperine, an Active Principle of Black and Long Peppers. Planta Med. 1993, 59, 413–417.
    35. Parise-Filho, R.; Pasqualoto, K.F.M.; Magri, F.M.M.; Ferreira, A.K.; da Silva, B.A.V.G.; Damião, M.C.F.C.B.; Tavares, M.T.; Azevedo, R.A.; Auada, A.V.V.; Polli, M.C.; et al. Dillapiole as Antileishmanial Agent: Discovery, Cytotoxic Activity and Preliminary SAR Studies of Dillapiole Analogues. Arch. Pharm. Pharm. Med. Chem. 2012, 345, 934–944.
    36. Pongkorpsakol, P.; Wongkrasant, P.; Kumpun, S.; Chatsudthipong, V.; Muanprasat, C. Inhibition of Intestinal Chloride Secretion by Piperine as a Cellular Basis for the Anti-Secretory Effect of Black Peppers. Pharmacol. Res. 2015, 100, 271–280.
    37. Ferreira, A.K.; de-Sá-Júnior, P.L.; Pasqualoto, K.F.M.; de Azevedo, R.A.; Câmara, D.A.D.; Costa, A.S.; Figueiredo, C.R.; Matsuo, A.L.; Massaoka, M.H.; Auada, A.V.V.; et al. Cytotoxic Effects of Dillapiole on MDA-MB-231 Cells Involve the Induction of Apoptosis through the Mitochondrial Pathway by Inducing an Oxidative Stress While Altering the Cytoskeleton Network. Biochimie 2014, 99, 195–207.
    38. Olmstead, R.G.; Bohs, L. A Summary of Molecular Systematic Research in Solanaceae: 1982-2006. Acta Hortic. 2007, 745, 255–268.
    39. Knapp, S. Tobacco to Tomatoes: A Phylogenetic Perspective on Fruit Diversity in the Solanaceae. J. Exp. Bot. 2002, 53, 2001–2022.
    40. Singh, B.; Gupta, V.; Bansal, P.; Singh, R.; Kumar, D. Pharmacological Potential of Plant Used as Aphrodisiacs. Int. J. Pharm. Sci. Rev. Res. 2010, 5, 104–113.
    41. Wannang, N.N.; Anuka, J.A.; Kwanashie, H.O.; Gyang, S.S.; Auta, A. Anti-Seizure Activity of the Aqueous Leaf Extract of Solanum Nigrum Linn (Solanaceae) in Experimental Animals. Afr. Health Sci. 2008, 8, 74–79.
    42. Ndebia, E.J.; Kamgang, R.; Nkeh-ChungagAnye, B.N. Analgesic and Anti-Inflammatory Properties of Aqueous Extract from Leaves of Solanum Torvum (Solanaceae). Afr. J. Tradit. Complement. Altern. Med. 2007, 4, 240–244.
    43. Monteiro, F.S.; Silva, A.C.L.; Martins, I.R.R.; Correia, A.C.C.; Basílio, I.J.L.D.; Agra, M.F.; Bhattacharyya, J.; Silva, B.A. Vasorelaxant Action of the Total Alkaloid Fraction Obtained from Solanum Paludosum Moric. (Solanaceae) Involves NO/CGMP/PKG Pathway and Potassium Channels. J. Ethnopharmacol. 2012, 141, 895–900.
    44. Gandhi, G.R.; Ignacimuthu, S.; Paulraj, M.G.; Sasikumar, P. Antihyperglycemic Activity and Antidiabetic Effect of Methyl Caffeate Isolated from Solanum Torvum Swartz. Fruit in Streptozotocin Induced Diabetic Rats. Eur. J. Pharmacol. 2011, 670, 623–631.
    45. Giorgetti, M.; Negri, G. Plants from Solanaceae Family with Possible Anxiolytic Effect Reported on 19thcentury’s Brazilian Medical Journal. Braz. J. Pharmacogn. 2011, 21, 772–780.
    46. Govindarajan, V.S. Capsicum-Production, Technology, Chemistry, and Quality Part 1: History, Botany, Cultivation, and Primary Processing. Crit. Rev. Food Sci. Nutr. 1985, 22, 109–176.
    47. Canto-Flick, A.; Balam-Uc, E.; Bello-Bello, J.J.; Lecona-Guzmán, C.; Solís-Marroquín, D.; Avilés-Viñas, S.; Gómez-Uc, E.; López-Puc, G.; Santana-Buzzy, N.; Iglesias-Andreu, L.G. Capsaicinoids Content in Habanero Pepper (Capsicum Chinense Jacq.): Hottest Known Cultivars. HortScience 2008, 43, 1344–1349.
    48. Gurnani, N.; Gupta, M.; Mehta, D.; Mehta, B.K. Chemical Composition, Total Phenolic and Flavonoid Contents, and in Vitro Antimicrobial and Antioxidant Activities of Crude Extracts from Red Chilli Seeds (Capsicum Frutescens L.)Gurnani, N.J. Taibah Univ. Sci. 2015, 10, 462–470.
    49. Zhuang, Y.; Chen, L.; Sun, L.; Cao, J. Bioactive Characteristics and Antioxidant Activities of Nine Peppers. J. Funct. Foods 2012, 4, 331–338.
    50. Oboh, G.; Puntel, R.L.; Rocha, J.B.T. Hot Pepper (Capsicum Annuum, Tepin and Capsicum Chinese, Habanero) Prevents Fe2+-Induced Lipid Peroxidation in Brain-in Vitro. Food Chem. 2007, 102, 178–185.
    51. Tundis, R.; Menichini, F.; Bonesi, M.; Conforti, F.; Statti, G.; Menichini, F.; Loizzo, M.R. Antioxidant and Hypoglycaemic Activities and Their Relationship to Phytochemicals in Capsicum Annuum Cultivars during Fruit Development. Lwt Food Sci. Technol. 2013, 53, 370–377.
    52. Zimmer, A.R.; Leonardi, B.; Miron, D.; Schapoval, E.; Oliveira, J.R.D.; Gosmann, G. Antioxidant and Anti-Inflammatory Properties of Capsicum Baccatum: From Traditional Use to Scientific Approach. J. Ethnopharmacol. 2012, 139, 228–233.
    53. Govindarajan, V.S.; Sathyanarayana, M.N. Capsicum—Production, Technology, Chemistry, and Quality. Part v. Impact on Physiology, Pharmacology, Nutrition, and Metabolism; Structure, Pungency, Pain, and Desensitization Sequences. Crit. Rev. Food Sci. Nutr. 1991, 29, 435–474.
    54. De Melo, J.G.; Santos, A.G.; De Amorim, E.L.C.; Nascimento, S.C.D.; De Albuquerque, U.P. Medicinal Plants Used as Antitumor Agents in Brazil: An Ethnobotanical Approach. Evid. Based Complement. Altern. Med. 2011, 2011, 1–11.
    55. Vasconcelos, T.N.C.; Lucas, E.J.; Brigido, P. One New Species, Two New Combinations and Taxonomic Notes on the All-Spice Genus Pimenta (Myrtaceae) from Hispaniola. Phytotaxa 2018, 348, 32–40.
    56. Gomes, S.M.; Dalla Nora Somavilla, N.S.; Gomes-Bezerra, K.M.; de Miranda, S.C.; De-Carvalhoa, P.S.; Graciano-Ribeiro, D. Leaf Anatomy of Myrtaceae Species: Contributions to the Taxonomy and Phylogeny. Acta Bot. Bras. 2009, 23, 223–238.
    57. Akin, M.; Aktumsek, A.; Nostro, A. Antibacterial Activity and Composition of the Essential Oils of Eucalyptus Camaldulensis Dehn. and Myrtus Communis L. Growing in Northern Cyprus. Afr. J. Biotechnol. 2010, 9, 531–535.
    58. Yokomizo, N.K.S.; Nakaoka-Sakita, M. Antimicrobial Activity and Essential Oils Yield of Pimenta Pseudocaryophyllus Var. Pseudocaryophyllus (Gomes) Landrum, Myrtaceae. Rev. Bras. Plantas Med. 2014, 16, 513–520.
    59. Weston, R.J. Bioactive Products from Fruit of the Feijoa (Feijoa Sellowiana, Myrtaceae): A Review. Food Chem. 2010, 121, 923–926.
    60. Myburg, A.A.; Grattapaglia, D.; Tuskan, G.A.; Hellsten, U.; Hayes, R.D.; Grimwood, J.; Jenkins, J.; Lindquist, E.; Tice, H.; Bauer, D.; et al. The Genome of Eucalyptus Grandis. Nature 2014, 510, 356–362.
    61. Ramos, A.; Visozo, A.; Piloto, J.; García, A.; Rodríguez, C.A.; Rivero, R. Screening of Antimutagenicity via Antioxidant Activity in Cuban Medicinal Plants. J. Ethnopharmacol. 2003, 87, 241–246.
    62. Paula, J.A.M.; Reis, J.B.; Ferreira, L.H.M.; Menezes, A.C.S.; Paula, J.R. Gênero Pimenta: Aspectos botânicos, composição química e potencial farmacológico. Rev. Bras. Plantas Med. 2010, 12, 363–379.
    63. Marzouk, M.S.A.; Moharram, F.A.; Mohamed, M.A.; Gamal-Eldeen, A.M.; Aboutabl, E.A. Anticancer and Antioxidant Tannins from Pimenta Dioica Leaves. Z. Nat. C 2007, 62, 526–536.
    64. Paula, J.A.M.D.; Silva, M.D.R.R.; Costa, M.P.; Diniz, D.G.A.; Sá, F.A.S.; Alves, S.F.; Costa, É.A.; Lino, R.C.; Paula, J.R. De Phytochemical Analysis and Antimicrobial, Antinociceptive, and Anti-Inflammatory Activities of Two Chemotypes of Pimenta Pseudocaryophyllus (Myrtaceae). Evid. Based Complement. Altern. Med. 2012.
    65. García, M.D.; Fernández, M.A.; Alvarez, A.; Saenz, M.T. Antinociceptive and Anti-Inflammatory Effect of the Aqueous Extract from Leaves of Pimenta Racemosa Var. Ozua (Mirtaceae). J. Ethnopharmacol. 2004, 91, 69–73.
    66. Padmakumari, K.P.; Sasidharan, I.; Sreekumar, M.M. Composition and Antioxidant Activity of Essential Oil of Pimento (Pimenta Dioica (L) Merr.) from Jamaica. Nat. Prod. Res. 2011, 25, 152–160.
    67. Kikuzaki, H.; Hara, S.; Kawai, Y.; Nakatani, N. Antioxidative Phenylpropanoids from Berries of Pimenta Dioica. Phytochemistry 1999, 52, 1307–1312.
    68. Seo, S.M.; Kim, J.; Lee, S.G.; Shin, C.H.; Shin, S.C.; Park, I.K. Fumigant Antitermitic Activity of Plant Essential Oils and Components from Ajowan (Trachyspermum Ammi), Allspice (Pimenta Dioica), Caraway (Carům Carvi), Dill (Anethum Graveoiens), Geranium (Pelargonium Graveoiens), and Litsea (Litsea Cubeba) Oils Against. J. Agric. Food Chem. 2009, 57, 6596–6602.
    69. Enoque, M.; Lima, L.; Cordeiro, I.; Cláudia, M.; Young, M.; Sobra, M.E.G.; Roberto, P.; Moreno, H. Antimicrobial Activity of the Essential Oil from Two Specimens of Pimenta Pseudocaryophyllus (Gomes) L. R. Landrum (Myrtaceae) Native from São Paulo State–Brazil. Pharmacologyonline 2006, 3, 589–593.
    70. Saenz, M.T.; Tornos, M.P.; Alvarez, A.; Fernandez, M.A.; García, M.D. Antibacterial Activity of Essential Oils of Pimenta Racemosa Var. Terebinthina and Pimenta Racemosa Var. Grisea. Fitoterapia 2004, 75, 599–602.
    71. Zabka, M.; Pavela, R.; Slezakova, L. Antifungal Effect of Pimenta Dioica Essential Oil against Dangerous Pathogenic and Toxinogenic Fungi. Ind. Crop. Prod. 2009, 30, 250–253.
    72. Wu, C.-C.C.; Bratton, S.B. Regulation of the Intrinsic Apoptosis Pathway by Reactive Oxygen Species. Antioxid. Redox Signal. 2012, 19, 121025083704002.
    73. Ouyang, L.; Shi, Z.; Zhao, S.; Wang, F.T.; Zhou, T.T.; Liu, B.; Bao, J.K. Programmed Cell Death Pathways in Cancer: A Review of Apoptosis, Autophagy and Programmed Necrosis. Cell Prolif. 2012, 45, 487–498.
    74. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The next Generation. Cell 2011, 144, 646–674.
    75. Liang, X.; Xu, K.; Xu, Y.; Liu, J.; Qian, X. B1-Induced Caspase-Independent Apoptosis in MCF-7 Cells Is Mediated by down-Regulation of Bcl-2 via P53 Binding to P2 Promoter TATA Box. Toxicol. Appl. Pharmacol. 2011, 256, 52–61.
    76. Thoennissen, N.H.; O’Kelly, J.; Lu, D.; Iwanski, G.B.; La, D.T.; Abbassi, S.; Leiter, A.; Karlan, B.; Mehta, R.; Koeffler, H.P. Capsaicin Causes Cell-Cycle Arrest and Apoptosis in ER-Positive and -Negative Breast Cancer Cells by Modulating the EGFR/HER-2 Pathway. Oncogene 2010, 29, 285–296.
    77. Elmore, S. Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 2007, 35, 495–516.
    78. McStay, G.P.; Green, D.R. Measuring Apoptosis: Caspase Inhibitors and Activity Assays. Cold Spring Harb. Protoc. 2014, 2014, 799–806.
    79. Roos, W.P.; Thomas, A.D.; Kaina, B. DNA Damage and the Balance between Survival and Death in Cancer Biology. Nat. Rev. Cancer 2015, 16, 20–33.
    80. Ashkenazi, A.; Fairbrother, W.J.; Leverson, J.D.; Souers, A.J. From Basic Apoptosis Discoveries to Advanced Selective BCL-2 Family Inhibitors. Nat. Rev. Drug Discov. 2017, 16, 273–284.
    81. Luo, X.; Budihardjo, I.; Zou, H.; Slaughter, C.; Wang, X. Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors. Cell 1998, 94, 481–490.
    82. Vyas, S.; Zaganjor, E.; Haigis, M.C. Mitochondria and Cancer. Cell 2016, 166, 555–566.
    83. Man, S.M.; Kanneganti, T. Converging Roles of Caspases in Inflammasome Activation, Cell Death and Innate Immunity. Nat. Rev. Immunol. 2016, 16, 7–21.
    84. Lopez, J.; Tait, S.W.G. Mitochondrial Apoptosis: Killing Cancer Using the Enemy Within. Br. J. Cancer 2015, 112, 957–962.
    85. Tsai, I.-L.; Lee, F.-P.; Wu, C.-C.; Duh, C.-Y.; Ishikawa, T.; Chen, J.-J.; Chen, Y.-C.; Seki, H.; Chen, I.-S. New Cytotoxic Cyclobutanoid Amides, a New Furanoid Lignan and Anti-Platelet Aggregation Constituents from Piper Arborescens. Planta Med. 2005, 71, 535–542.
    86. Kim, K.H.; Kim, H.K.; Choi, S.U.; Moon, E.; Kim, S.Y.; Lee, K.R. Bioactive Lignans from the Rhizomes of Acorus Gramineus. J. Nat. Prod. 2011, 74, 2187–2192.
    87. Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; Léonce, S.; Pfeiffer, B.; Renard, P. Synthesis and Biological Evaluation of Aristolactams. Bioorg. Med. Chem. Lett. 2002, 12, 3557–3559.
    88. Punganuru, S.R.; Madala, H.R.; Venugopal, S.N.; Samala, R.; Mikelis, C.; Srivenugopal, K.S. Design and Synthesis of a C7-Aryl Piperlongumine Derivative with Potent Antimicrotubule and Mutant P53-Reactivating Properties. Eur. J. Med. Chem. 2016, 107, 233–244.
    89. Hegde, V.R.; Borges, S.; Pu, H.; Patel, M.; Gullo, V.P.; Wu, B.; Kirschmeier, P.; Williams, M.J.; Madison, V.; Fischmann, T.; et al. Semi-Synthetic Aristolactams--Inhibitors of CDK2 Enzyme. Bioorg. Med. Chem. Lett. 2010, 20, 1384–1387.
    90. Chang-Yih, D.; Yang-Chang, W.; Shang-Kwei, W. Cytotoxic Pyridone Alkaloids from Piper Aborescens. Phytochemistry 1990, 29, 2689–2691.
    91. Bezerra, D.P.; Pessoa, C.; Moraes, M.O.d.; Silveira, E.R.; Lima, M.A.S.; Martins Elmiro, F.J.; Costa-Lotufo, L.V. Antiproliferative Effects of Two Amides, Piperine and Piplartine, from Piper Species. Z. Nat. C 2005, 60, 539–543.
    92. Bezerra, D.P.; Militão, G.C.G.; de Castro, F.O.; Pessoa, C.; de Moraes, M.O.; Silveira, E.R.; Lima, M.A.S.; Elmiro, F.J.M.; Costa-Lotufo, L.V. Piplartine Induces Inhibition of Leukemia Cell Proliferation Triggering Both Apoptosis and Necrosis Pathways. Toxicol. Vitr. Int. J. Publ. Assoc. Bibra 2007, 21, 1–8.
    93. Wu, Y.; Min, X.; Zhuang, C.; Li, J.; Yu, Z.; Dong, G.; Yao, J.; Wang, S.; Liu, Y.; Wu, S.; et al. Design, Synthesis and Biological Activity of Piperlongumine Derivatives as Selective Anticancer Agents. Eur. J. Med. Chem. 2014, 82, 545–551.
    94. Sommerwerk, S.; Kluge, R.; Ströhl, D.; Heller, L.; Kramell, A.E.; Ogiolda, S.; Liebing, P.; Csuk, R. Synthesis, Characterization and Cytotoxicity of New Piplartine Dimers. Tetrahedron 2016, 72, 1447–1454.
    95. Nerurkar, P.V.; Dragull, K.; Tang, C.-S.S. In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones. Toxicol. Sci. Off. J. Soc. Toxicol. 2004, 79, 106–111.
    96. Sriwiriyajan, S.; Sukpondma, Y.; Srisawat, T.; Madla, S.; Graidist, P. (−)-Kusunokinin and Piperloguminine from Piper Nigrum: An Alternative Option to Treat Breast Cancer. Biomed. Pharmacother. 2017, 92, 732–743.
    97. Ee, G.C.L.; Lim, C.M.; Rahmani, M.; Shaari, K.; Bong, C.F.J. Pellitorine, a Potential Anti-Cancer Lead Compound against HL60 and MCT-7 Cell Lines and Microbial Transformation of Piperine from Piper Nigrum. Molecules 2010, 15, 2398–2404.
    98. Gutierrez, R.M.P.; Gonzalez, A.M.N.; Hoyo-Vadillo, C. Alkaloids from Piper: A Review of Its Phytochemistry and Pharmacology. Mini Rev. Med. Chem. 2013, 13, 163–193.
    99. Chen, J.; Duh, C.; Huang, H.; Chen, I. Cytotoxic Constituents of Piper Sintenense. Helv. Chim. Acta 2003, 86, 2058–2064.
    100. Rao, V.R.S.; Suresh, G.; Rao, R.R.; Babu, K.S.; Chashoo, G.; Saxena, A.K.; Rao, J.M.; Rama Subba Rao, V.; Suresh, G.; Ranga Rao, R.; et al. Synthesis of Piperine-Amino Acid Ester Conjugates and Study of Their Cytotoxic Activities against Human Cancer Cell Lines. Med. Chem. Res. 2012, 21, 38–46.
    101. Umadevi, P.; Deepti, K.; Venugopal, D.V.R. Synthesis, Anticancer and Antibacterial Activities of Piperine Analogs. Med. Chem. Res. 2013, 22, 5466–5471.
    102. Lin, Y.; Xu, J.; Liao, H.; Li, L.; Pan, L. Piperine Induces Apoptosis of Lung Cancer A549 Cells via P53-Dependent Mitochondrial Signaling Pathway. Tumor Biol. 2014, 35, 3305–3310.
    103. Muharini, R.; Liu, Z.; Lin, W.; Proksch, P. New Amides from the Fruits of Piper Retrofractum. Tetrahedron Lett. 2015, 56, 2521–2525.
    104. Orjala, J.; Wright, A.; Rali, T.; Sticher, O. Aduncamide, a Cytotoxic and Antibacterial β-Phenylethylamine-Derived Amide from Piper Aduncum. Nat. Prod. Lett. 1993, 2, 231–236.
    105. Rali, T.; Wossa, S.W.; Leach, D.N.; Waterman, P.G. Volatile Chemical Constituents of Piper Aduncum L and Piper Gibbilimbum C. DC (Piperaceae) from Papua New Guinea. Molecules 2007, 12, 389–394.
    106. Chen, I.S.; Chen, Y.C.; Liao, C.H. Amides with Anti-Platelet Aggregation Activity from Piper Taiwanense. Fitoterapia 2007, 78, 414–419.
    107. Rao, V.R.S.; Suresh, G.; Babu, K.S.; Raju, S.S.; Vishnu Vardhan, M.V.P.S.P.S.; Ramakrishna, S.; Rao, J.M. Novel Dimeric Amide Alkaloids from Piper Chaba Hunter: Isolation, Cytotoxic Activity, and Their Biomimetic Synthesis. Tetrahedron 2011, 67, 1885–1892.
    108. Ren, J.; Xu, Y.; Huang, Q.; Yang, J.; Yang, M.; Hu, K.; Wei, K. Chabamide Induces Cell Cycle Arrest and Apoptosis by the Akt/MAPK Pathway and Inhibition of P-Glycoprotein in K562/ADR Cells. Anti Cancer Drugs 2015, 26, 498–507.
    109. Tabudravu, J.N.; Jaspars, M. Anticancer Activities of Constituents of Kava (Piper Methysticum). South Pac. J. Nat. Appl. Sci. 2005, 23, 26–29.
    110. Amaral, P.D.A.; Petrignet, J.; Gouault, N.; Agustini, T.; Lohézic-Ledévéhat, F.; Cariou, A.; Grée, R.; Eifler-Lima, V.L.; David, M. Synthesis of Novel Kavain-like Derivatives and Evaluation of Their Cytotoxic Activity. J. Braz. Chem. Soc. 2009, 20, 1687–1697.
    111. Abu, N.; Akhtar, M.N.; Yeap, S.K.; Lim, K.L.; Ho, W.Y.; Zulfadli, A.J.; Omar, A.R.; Sulaiman, M.R.; Abdullah, M.P.; Alitheen, N.B. Flavokawain A Induces Apoptosis in MCF-7 and MDA-MB231 and Inhibits the Metastatic Process In Vitro. PLoS ONE 2014, 9, e105244.
    112. Thieury, C.; Lebouvier, N.; Le Gu??vel, R.; Barguil, Y.; Herbette, G.; Antheaume, C.; Hnawia, E.; Asakawa, Y.; Nour, M.; Guillaudeux, T. Mechanisms of Action and Structure-Activity Relationships of Cytotoxic Flavokawain Derivatives. Bioorg. Med. Chem. 2017, 25, 1817–1829.
    113. Tang, Y.; Li, X.; Liu, Z.; Simoneau, A.R.; Xie, J.; Zi, X. Flavokawain B, a Kava Chalcone, Induces Apoptosis via up-Regulation of Death-Receptor 5 and Bim Expression in Androgen Receptor Negative, Hormonal Refractory Prostate Cancer Cell Lines and Reduces Tumor Growth. Int. J. Cancer. 2010, 127, 1758–1768.
    114. Zhao, X.; Chao, Y.-L.; Wan, Q.-B.; Chen, X.-M.; Su, P.; Sun, J.; Tang, Y. Flavokawain B Induces Apoptosis of Human Oral Adenoid Cystic Cancer ACC-2 Cells via up-Regulation of Bim and down-Regulation of Bcl-2 Expression. Can. J. Physiol. Pharmacol. 2011, 89, 875–883.
    115. Hseu, Y.-C.; Lee, M.-S.; Wu, C.-R.; Cho, H.-J.; Lin, K.-Y.; Lai, G.-H.; Wang, S.-Y.; Kuo, Y.-H.; Kumar, K.J.S.; Yang, H.-L.; et al. The Chalcone Flavokawain B Induces G2/M Cell-Cycle Arrest and Apoptosis in Human Oral Carcinoma HSC-3 Cells through the Intracellular ROS Generation and Downregulation of the Akt/P38 MAPK Signaling Pathway. J. Agric. Food Chem. 2012, 60, 2385–2397.
    116. Eskander, R.N.; Randall, L.M.; Sakai, T.; Guo, Y.; Hoang, B.; Zi, X. Flavokawain B, a Novel, Naturally Occurring Chalcone, Exhibits Robust Apoptotic Effects and Induces G2/M Arrest of a Uterine Leiomyosarcoma Cell Linejog. J. Obstet. Gynaecol. Res. 2012, 38, 1086–1094.
    117. An, J.; Gao, Y.; Wang, J.; Zhu, Q.; Ma, Y.; Wu, J.; Sun, J.; Tang, Y. Flavokawain B Induces Apoptosis of Non-Small Cell Lung Cancer H460 Cells via Bax-Initiated Mitochondrial and JNK Pathway. Biotechnol. Lett. 2012, 34, 1781–1788.
    118. Jandial, D.D.; Krill, L.S.; Chen, L.; Wu, C.; Ke, Y.; Xie, J.; Hoang, B.H.; Zi, X. Induction of G2M Arrest by Flavokawain a, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules 2017, 22, 462.
    119. Zi, X.; Simoneau, A.R. Flavokawain A, a Novel Chalcone from Kava Extract, Induces Apoptosis in Bladder Cancer Cells by Involvement of Bax Protein-Dependent and Mitochondria-Dependent Apoptotic Pathway and Tumor Growth in Mice. Cancer Res. 2005, 65, 3479–3486.
    120. Phang, C.-W.; Karsani, S.A.; Sethi, G.; Abd Malek, S.N. Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells. PLoS ONE 2016, 11, e0148775.
    121. Nurestri, S.; Malek, A.; Phang, C.W.; Ibrahim, H.; Wahab, N.A.; Sim, K.S. Phytochemical and Cytotoxic Investigations of Alpinia Mutica Rhizomes. Molecules 2011, 16, 583–589.
    122. Valadares, M.C.; de Carvalho, I.C.T.; de Oliveira Junior, L.; Vieira, M.D.S.; Benfica, P.L.; de Carvalho, F.S.; Andrade, L.V.S.; Lima, E.M.; Kato, M.J. Cytotoxicity and Antiangiogenic Activity of Grandisin. J. Pharm. Pharmacol. 2009, 61, 1709–1714.
    123. Ferreira, I.R.S. Evaluation of Cytotoxicity of Phytochemicals in V79 Cells and Inhibition of Cell Growth in Human Leukemic Cells; Campinas State University: São Paulo, Brazil, 2014.
    124. Vieira, M.d.S.; de Oliveira, V.; Lima, E.M.; Kato, M.J.; Valadares, M.C. In Vitro Basal Cytotoxicity Assay Applied to Estimate Acute Oral Systemic Toxicity of Grandisin and Its Major Metabolite. Exp. Toxicol. Pathol. 2011, 63, 505–510.
    125. Jiang, Z.H.; Liu, Y.P.; Huang, Z.H.; Wang, T.T.; Feng, X.Y.; Yue, H.; Guo, W.; Fu, Y.H. Cytotoxic Dihydrobenzofuran Neolignans from Mappianthus Iodoies. Bioorg. Chem. 2017, 75, 260–264.
    126. Sawasdee, K.; Chaowasku, T.; Lipipun, V.; Dufat, T.-H.; Michel, S.; Likhitwitayawuid, K. Neolignans from Leaves of Miliusa Mollis. Fitoterapia 2013, 85, 49–56.
    127. Longato, G.B.; Rizzo, L.Y.; De Oliveira Sousa, I.M.; Tinti, S.V.; Possenti, A.; Figueira, G.M.; Ruiz, A.L.T.G.; Foglio, M.A.; De Carvalho, J.E. In Vitro and in Vivo Anticancer Activity of Extracts, Fractions, and Eupomatenoid-5 Obtained from Piper Regnellii Leaves. Planta Med. 2011, 77, 1482–1488.
    128. Bley, K.; Boorman, G.; Mohammad, B.; McKenzie, D.; Babbar, S. A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin. Toxicol. Pathol. 2012, 40, 847–873.
    129. De-Sá-Júnior, P.L.; Pasqualoto, K.F.M.; Ferreira, A.K.; Tavares, M.T.; Damião, M.C.F.C.B.; De Azevedo, R.A.; Câmara, D.A.D.; Pereira, A.; De Souza, D.M.; Parise Filho, R. RPF101, A New Capsaicin-like Analogue, Disrupts the Microtubule Network Accompanied by Arrest in the G2/M Phase, Inducing Apoptosis and Mitotic Catastrophe in the MCF-7 Breast Cancer Cells. Toxicol. Appl. Pharmacol. 2013, 266, 385–398.
    130. Damião, M.C.F.C.B.; Pasqualoto, K.F.M.; Ferreira, A.K.; Teixeira, S.F.; Azevedo, R.A.; Barbuto, J.A.M.; Palace-Berl, F.; Franchi-Junior, G.C.; Nowill, A.E.; Tavares, M.T.; et al. Novel Capsaicin Analogues as Potential Anticancer Agents: Synthesis, Biological Evaluation, and In Silico Approach. Arch. Der Pharm. 2014, 347, 885–895.
    131. Ferreira, A.K.; Tavares, M.T.; Pasqualoto, K.F.M.; de Azevedo, R.A.; Teixeira, S.F.; Ferreira-Junior, W.A.; Bertin, A.M.; de-Sá-Junior, P.L.; Barbuto, J.A.M.; Figueiredo, C.R.; et al. RPF151, a Novel Capsaicin-like Analogue: In Vitro Studies and in Vivo Preclinical Antitumor Evaluation in a Breast Cancer Model. Tumor Biol. 2015.
    132. Tavares, M.T. Novel Anticancer Candidates: Synthesis and Antitumor Activity of Capsaicin-like Sulfonate and Sulfonamide Analogues; University of Sao Paulo: São Paulo, Brazil, 2014.
    133. Batista Fernandes, T.; Alexandre de Azevedo, R.; Yang, R.; Fernandes Teixeira, S.; Henrique Goulart Trossini, G.; Alexandre Marzagao Barbuto, J.; Kleber Ferreira, A.; Parise Filho, R. Arylsulfonylhydrazone Induced Apoptosis in MDA-MB-231 Breast Cancer Cells. Lett. Drug Des. Discov. 2018, 15.
    134. Pereira, G.J.V.; Tavares, M.T.; Azevedo, R.A.; Martins, B.B.; Cunha, M.R.; Bhardwaj, R.; Cury, Y.; Zambelli, V.O.; Barbosa, E.G.; Hediger, M.A.; et al. Capsaicin-like Analogue Induced Selective Apoptosis in A2058 Melanoma Cells: Design, Synthesis and Molecular Modeling. Bioorg. Med. Chem. 2019, 27, 2893–2904.
    135. Kotake-Nara, E.; Kushiro, M.; Zhang, H.; Sugawara, T.; Miyashita, K.; Nagao, A. Carotenoids Affect Proliferation of Human Prostate Cancer Cells. J. Nutr. 2001, 131, 3303–3306.
    136. Molnár, J.; Serly, J.; Pusztai, R.; Vincze, I.; Molnár, P.; Horváth, G.; Deli, J.; Maoka, T.; Zalatnai, A.; Tokuda, H.; et al. Putative Supramolecular Complexes Formed by Carotenoids and Xanthophylls with Ascorbic Acid to Reverse Multidrug Resistance in Cancer Cells. Anticancer Res. 2012, 32, 507–517.
    137. Zhang, L.; Shamaladevi, N.; Jayaprakasha, G.K.; Patil, B.S.; Lokeshwar, B.L. Polyphenol-Rich Extract of Pimenta Dioica Berries (Allspice) Kills Breast Cancer Cells by Autophagy and Delays Growth of Triple Negative Breast Cancer in Athymic Mice. Oncotarget 2015, 6, 16379–16395.
    More