Phytochemicals Targeting Endoplasmic Reticulum Stress to Inhibit Cancer Cell Proliferation

  • Sukriti Srivastava
  • Gauransh Jain
  • Shweta Dang
  • Sanjay Gupta
  • Reema GabraniEmail author


Cancer is marked by uncontrolled cell proliferation avoiding the programmed cell death. Rapid cell division demands increased protein synthesis, overloading endoplasmic reticulum (ER) machinery with enhanced folding, packaging and transportation of proteins causing ER stress. Unfolded protein response (UPR), the adaptive pathway activated by the cell in response to this stress, promotes survival of the cancer cells and hence tumorigenesis. The duration and severity of stress determine the fate of the cell, that is, whether the cell will survive and follow adaptive response or it will lead to apoptosis. Targeting the ER chaperones, UPR machinery and elements that assist in protein folding in the ER lumen might provide a significant therapeutic target against cancer. Phytochemicals can modulate various cellular functions and have been promising agents against cancer. The aim of this chapter is to summarize the possible impact of various phytochemicals like carnosic acid, diallyl sulphur compounds, gambogic acid, galangin, pachymic acid, pomegranate fruit extract, proanthocyanidins and resveratrol, Saccharina japonica n-hexane fraction, 6-shogaol and sulphureuin B, which has the ability to alter ER stress. The anti-proliferative mechanisms of these phytochemicals and their impact on ER stress and cancer progression have also been discussed.


Apoptosis Cancer ER chaperones ER stress Phytochemicals UPR 


  1. Berrington D, Lall N (2012) Anticancer activity of certain herbs and spices on the cervical epithelial carcinoma (HeLa) cell line. Evid Based Compl Altern Med 2012:564927. CrossRefGoogle Scholar
  2. Biswas J, Roy M, Mukherjee A (2015) Anticancer drug development based on phytochemicals. J Drug Discovery Dev Deliv 2:1012–1017Google Scholar
  3. Cao SS, Kaufman RJ (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 21:396–413CrossRefPubMedPubMedCentralGoogle Scholar
  4. Carreras S, Pihan P, Hetz C (2017) The unfolded protein response: at the intersection between endoplasmic reticulum function and mitochondrial bioenergetics. Front Oncol 7:55. CrossRefGoogle Scholar
  5. Chen Q, Liu XF, Zheng PS (2014) Grape seed proanthocyanidins (GSPs) inhibit the growth of cervical cancer by inducing apoptosis mediated by the mitochondrial pathway. PLoS One 9:e107045. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cheng S, Swanson K, Eliaz I, McClintick JN, Sandusky GE, Sliva D (2015) Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. PLoS One 10:e0122270. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Corazzari M, Gagliardi M, Fimia GM, Piacentini M (2017) Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front Oncol 7:78. CrossRefPubMedPubMedCentralGoogle Scholar
  8. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Exp Opin Ther Targets 16:S17–S27CrossRefGoogle Scholar
  9. Derry M, Somasagara RR, Raina K, Kumar S, Gomez J, Patel M, Agarwal R, Agarwal C (2014) Target identification of grape seed extract in colorectal cancer using drug affinity responsive target stability (DARTS) technique: role of endoplasmic reticulum stress response proteins. Curr Cancer Drug Targets 14:323–336CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dinicola S, Cucina A, Pasqualato A, Proietti S, D’Anselmi F, Pasqua G, Santamaria AR, Coluccia P, Laganà A, Antonacci D, Giuliani A, Bizzarri M (2010) Apoptosis-inducing factor and caspase-dependent apoptotic pathways triggered by different grape seed extracts on human colon cancer cell line Caco-2. Br J Nutr 104:824–832CrossRefPubMedGoogle Scholar
  11. Farooqi AA, Li KT, Fayyaz S, Chang YT, Ismail M, Liaw CC, Yuan SS, Tang JY, Chang HW (2015) Anticancer drugs for the modulation of endoplasmic reticulum stress and oxidative stress. Tumor Biol 36:5743–5752CrossRefGoogle Scholar
  12. Flaumenhaft R, Furie B, Zwicker JL (2015) Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease. Arterioscler Thromb Vasc Biol 35:16–23CrossRefPubMedGoogle Scholar
  13. Gullett NP, Ruhul Amin AR, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O (2010) Cancer prevention with natural compounds. Semin Oncol 37:258–281CrossRefPubMedGoogle Scholar
  14. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15:481–490CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hausmann SC, Vlachojannis C, Zimmermann B (2014) Pomegranate juice and prostate cancer: importance of the characterisation of the active principle. Phytother Res 28:1676–1678CrossRefGoogle Scholar
  16. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102CrossRefGoogle Scholar
  17. Hiramatsu N, Messah C, Han J, LaVail MM, Kaufman RJ, Lin JH (2014) Translational and post translational regulation of XIAP by eIF2α and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25:1411–1420CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hu R, Zhou P, Peng YB, Xu X, Ma J, Liu Q, Zhang L, Wen XD, Qi LW, Gao N, Li P (2012) 6-Shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress. PLoS One 7:e39664. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Jing WZ, Gong LW, Zhang L, Duan DM, Ren ZR (2015) Sulphureuine B, a drimane type sesquiterpenoid isolated from Laetiporus sulphureus induces apoptosis in glioma cells. Bangladesh J Pharmacol 10:844–853CrossRefGoogle Scholar
  21. Jo MJ, Kim HR, Kim GD (2012) The anticancer effects of Saccharina japonica on 267B1/K-ras human prostate cancer cells. Int J Oncol 41:1789–1797CrossRefPubMedGoogle Scholar
  22. Jun M, Jun L, Chunwei L, Dingfang C (2015) Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells. Cancer Cell Int 15:1475–1486Google Scholar
  23. Jung I, Jo MJ, Kim HR, Choi YH, Kim GD (2014) Extract of Saccharina japonica induces apoptosis companied by cell cycle arrest and endoplasmic reticulum stress in SK-Hep1 human hepatocellular carcinoma cells. Asian Pac J Cancer Prev 15:2993–2999CrossRefGoogle Scholar
  24. Kato H, Nishitoh H (2015) Stress responses from the endoplasmic reticulum in cancer. Front Oncol 5:e00093CrossRefGoogle Scholar
  25. Khan N, Mukhtar H (2015) Dietary agents for prevention and treatment of lung cancer. Cancer Lett 359:155–164CrossRefPubMedPubMedCentralGoogle Scholar
  26. Krajarng A, Imoto M, Tashiro E, Fujimaki T, Shinjo S, Watanapokasin R (2015) Apoptosis induction associated with the ER stress response through up-regulation of JNK in HeLa cells by gambogic acid. BMC Complement Altern Med 15:26. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lamoureux F, Thomas C, Yin MJ, Fazli L, Zoubeidi A, Gleave ME (2014) Suppression of heat shock protein 27 using OGX-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer. Eur Urol 66:145–155CrossRefPubMedGoogle Scholar
  28. Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R, Ng KY (2010) Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in non small cell lung cancer A549 cells. Mol Carcinog 49:271–282PubMedGoogle Scholar
  29. Liu Q, Peng YB, Zhou P, Qi LW, Zhang M, Gao N, Liu EH, Li P (2013) 6-Shogaol induces apoptosis in human leukemia cells through a process involving caspase-mediated cleavage of eIF2α. Mol Cancer Biol 12:1–12CrossRefGoogle Scholar
  30. Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L (2011) Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harb Perspect Biol 3:a004317CrossRefPubMedPubMedCentralGoogle Scholar
  31. Min KJ, Jung KJ, Kwon TK (2014) Carnosic acid induces apoptosis through reactive oxygen species-mediated endoplasmic reticulum stress induction in human renal carcinoma caki cells. J Cancer Prev 19:170–178CrossRefPubMedPubMedCentralGoogle Scholar
  32. Nicastro HL, Ross SA, Milner JA (2015) Garlic and onions: their cancer prevention properties. Cancer Prev Res 8:181–189CrossRefGoogle Scholar
  33. Ojha R, Amaravadi RK (2017) Targeting the unfolded protein response in cancer. Pharmacol Res 2017:1–31Google Scholar
  34. Omar SH, Al-Wabel NA (2010) Organosulfur compounds and possible mechanism of garlic in cancer. Saudi Pharm J 18:51–58CrossRefPubMedGoogle Scholar
  35. Park JE, Park B, Chae IG, Kim DH, Kundu J, Kundu JK, Chun KS (2016) Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma caki cells. Oncol Rep 35:2723–2732CrossRefPubMedGoogle Scholar
  36. Perri ER, Thomas CJ, Parakh S, Spencer DM, Atkin JD (2016) The unfolded protein response and the role of protein disulfide isomerase in neurodegeneration. Front Cell Dev Biol 3:80. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Petiwala SM, Puthenveetil AG, Johnson JJ (2013) Polyphenols from the mediterranean herb rosemary (Rosmarinus officinalis) for prostate cancer. Front Pharmacol 4:29. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Petiwala SM, Berhe S, Li G, Puthenveetil AG, Rahman O, Nonn L, Johnson JJ (2014) Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth. PLoS One 9:e89772. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Petiwala SM, Li G, Bosland MC, Lantvit DD, Petukhov PA, Johnson JJ (2016) Carnosic acid promotes degradation of the androgen receptor and is regulated by the unfolded protein response pathway in vitro and in vivo. Carcinogenesis 37:827–838CrossRefPubMedGoogle Scholar
  40. Quick Q, Faison MO (2012) CHOP and caspase-3 induction underlie glioblastoma cell death in response to endoplasmic reticulum stress. Exp Ther Med 3:487–492CrossRefPubMedGoogle Scholar
  41. Schonthal AH (2012) Targeting endoplasmic reticulum stress for cancer therapy. Front Biosci 4:412–431CrossRefGoogle Scholar
  42. Schwarz DS, Blower MD (2016) The endoplasmic reticulum: structure, function and response to cellular signalling. Cell Mol Life Sci 73:79–94CrossRefPubMedGoogle Scholar
  43. Sharma P, McClees SF, Afaq F (2017) Pomegranate for prevention and treatment of cancer: an update. Molecules 22:1–18CrossRefGoogle Scholar
  44. Song TL, Min HL, Lan HC, Ting FW, Li HC, Gwo IL (2013) Suppression of urinary bladder urothelial carcinoma cell by the ethanol extract of pomegranate fruit through cell cycle arrest and apoptosis. BMC Complement Altern Med 13:364. CrossRefGoogle Scholar
  45. Song Y, Wang Q, He Y, Ren D, Kow F, Li J, Liu S, Cong H (2017) The positive effects of fucoidans extracted from the brown seaweed Saccharina japonica on protection against CCl4-induced liver injury. J Appl Phycol 29:2077–2087CrossRefGoogle Scholar
  46. Su L, Chen X, Wu J, Lin B, Zhang H, Lan L, Luo H (2013) Galangin inhibits proliferation of hepatocellular carcinoma cells by inducing endoplasmic reticulum stress. Food Chem Toxicol 62:810–816CrossRefPubMedGoogle Scholar
  47. Su K, Wang CF, Zhang Y, Cai YJ, Zhang YY, Zhao Q (2016) The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway. Biomed Pharmaco Ther 82:180–191CrossRefGoogle Scholar
  48. Tang Q, Lu M, Zhou H, Chen D, Liu L (2017) Gambogic acid inhibits the growth of ovarian cancer tumors by regulating p65 activity. Oncol Lett 13:384–388CrossRefPubMedGoogle Scholar
  49. Tung Y, Tsai ML, Kuo FL, Lai CS, Badmaev V, Ho CT, Pan MH (2015) Se-methyl-L-selenocysteine induces apoptosis via endoplasmic reticulum stress and the death receptor pathway in human colon adenocarcinoma COLO 205 cells. J Agric Food Chem 63:5008–5016CrossRefPubMedGoogle Scholar
  50. Urra H, Dufey E, Avril T, Chevet E, Hetz C (2016) Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer 2:52–62CrossRefGoogle Scholar
  51. Vandewynckel PY, Laukens D, Geerts A, Bogaerts E, Paridaens A, Verhelst X, Janssens S, Heindryckx F, Van Vlierberghe H (2016) The paradox of the unfolded protein response in cancer. Anticancer Res 33:4683–4694Google Scholar
  52. Venkatesan R, Ji E, Kim SY (2015) Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review. Biomed Res Int 814068:1–22CrossRefGoogle Scholar
  53. Vicinanza R, Zhang Y, Henning SM, Heber D (2013) Pomegranate juice metabolites, ellagic acid and urolithin A, synergistically inhibit androgenindependent prostate cancer cell growth via distinct effects on cell cycle control and apoptosis. Evid Based Complement Alternat Med 2013:247504. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Wang M, Kaufman RJ (2014) The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 14:581–597CrossRefGoogle Scholar
  55. Wang HC, Pao J, Lin SY, Sheen LY (2012a) Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression. Ann New York Acad Sci 1271:44–52CrossRefGoogle Scholar
  56. Wang SB, Shi Q, Xu Y, Xie WL, Zhang J, Tian C, Guo Y, Wang K, Zhang BY, Chen C, Gao C, Dong XP (2012b) Protein disulfide isomerase regulates endoplasmic reticulum stress and the apoptotic process during prion infection and PrP mutant induced cytotoxicity. PLoS One 7:e38221. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Wang WA, Groenendyk J, Michalak M (2014) Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta 1843:2143–2149CrossRefPubMedGoogle Scholar
  58. Wen C, Huang L, Chen J, Lin M, Li W, Lu B, Rutnam ZY, Iwamoto A, Wang Z, Yang X, Liu H (2015) Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells. Int J Oncol 47:1663–1671CrossRefPubMedPubMedCentralGoogle Scholar
  59. Weng C, Chou CP, Ho CT, Yen GC (2012) Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Mol Nutr Food Res 56:1304–1313CrossRefPubMedGoogle Scholar
  60. Wu XJ, Kassie F, Mersch-Sundermann V (2005) The role of reactive oxygen species (ROS) production on diallyl disulfide (DADS) induced apoptosis and cell cycle arrest in human A549 lung carcinoma cells. Mutat Res 579:115–124CrossRefPubMedGoogle Scholar
  61. Wu JJ, Omar HA, Lee YR, Teng YN, Chen PS, Chen YC, Huang HS, Lee KH, Hung JH (2015a) 6-Shogaol induces cell cycle arrest and apoptosis in human hepatoma cells through pleiotropic mechanisms. Eur J Pharmacol 762:449–458CrossRefPubMedGoogle Scholar
  62. Wu S, Zhou Y, Yang G, Tian H, Geng Y, Hu Y, Lin K, Wu W (2017) Sulforaphane-cysteine induces apoptosis by sustained activation of ERK1/2 and caspase 3 in human glioblastoma U373MG and U87MG cells. Oncol Rep 37:829–838Google Scholar
  63. Xu S, Sankar S, Neamati N (2014) Protein disulfide isomerase: a promising target for cancer therapy. Drug Discov Today 19:222–240CrossRefPubMedGoogle Scholar
  64. Yang Y, Karakhanova S, Werner J, Bazhin AV (2013) Reactive oxygen species in cancer biology and anticancer therapy. Curr Med Chem 20:3677–3692CrossRefPubMedGoogle Scholar
  65. Zhang L (2010) Gambogic acid inhibits Hsp90 and deregulates TNF-α/NF-κB in HeLa cells. Biochem Biophys Res Commun 403:282–287CrossRefPubMedGoogle Scholar
  66. Zhang HT, Wu J, Wen M, LJ S, Luo H (2012) Galangin induces apoptosis in hepatocellular carcinoma cells through the caspase 8/t-Bid mitochondrial pathway. J Asian Nat Prod Res 14:626–633CrossRefPubMedGoogle Scholar
  67. Zhang JW, Wen GL, Zhang L, Duan DM, Ren ZH (2015) Sulphureuine B, a drimane type sesquiterpenoid isolated from Laetiporus sulphureus induces apoptosis in glioma cells. Bangladesh J Pharmacol 10:844CrossRefGoogle Scholar
  68. Zorzi E, Bonvini P (2011) Inducible hsp70 in the regulation of cancer cell survival: analysis of chaperone induction, expression and activity. Cancers 3:3921–3956CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Sukriti Srivastava
    • 1
  • Gauransh Jain
    • 1
  • Shweta Dang
    • 1
  • Sanjay Gupta
    • 1
  • Reema Gabrani
    • 1
    Email author
  1. 1.Department of BiotechnologyJaypee Institute of Information TechnologyNoidaIndia

Personalised recommendations