Skip to main content
SpringerLink
Log in

Kaempferol Induces Cell Death and Sensitizes Human Head and Neck Squamous Cell Carcinoma Cell Lines to Cisplatin

  • Chapter
  • First Online:
Cell Biology and Translational Medicine, Volume 12

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1326))

Abstract

Cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with head and neck cancer; nevertheless, cisplatin resistance poses a main challenge for its clinical efficacy. Recent studies have shown that kaempferol, a natural flavonoid found in various plants and foods, has an anticancer effect. The following study evaluated the cytotoxic effects of kaempferol on head and neck tumor cells and their mechanism of action, evaluating the effects on proliferation, the oxygen consumption rate, transmembrane potential, tumor cell migration and induction of apoptosis. Moreover, we determined the effects of a combination of kaempferol and cisplatin on head and neck tumor cells. We found that kaempferol inhibited the oxygen consumption rate and decreased the intracellular ATP content in tumor cells. This novel mechanism may inhibit the migratory capacity and promote antiproliferative effects and apoptosis of tumor cells. Additionally, our in vitro data indicated that kaempferol may sensitize head and neck tumor cells to the effects of cisplatin. These effects provide new evidence for the use of a combination of kaempferol and cisplatin in vivo and their future applications in head and neck cancer therapy.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AKT:

Protein kinase B

AV:

Annexin V

CCCP:

Carbonyl cyanide m-chlorophenyl hydrazone

CoQ:

Coenzyme Q

CSC:

Cancer stem cells

DOK:

Dysplastic oral keratinocytes

EGFR:

epidermal growth factor receptor

ETC:

Electron transport chain

HNSCC:

Head and neck squamous cell carcinomas

IC50:

Concentration necessary to achieve 50% viability inhibition.

MMP-2:

Metalloproteinase-2

MMP-9:

Metalloproteinase-9

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OCR:

Oxygen consume rate

OxPhos:

Oxidative phosphorylation

PI:

Propidium iodide

PI3K:

Phosphatidylinositol 3-kinases

PTEN:

Phosphatase and tensin homolog protein

TMRME:

Tetra methyl rhodamine methyl ester

VEGF:

Vascular endothelial growth factor

ΔΨm:

Mitochondrial transmembrane potential

References

  • Abdal Dayem A, Choi HY, Yang GM, Kim K, Saha SK, Cho SG (2016) The anti-cancer effect of polyphenols against breast cancer and cancer stem cells: molecular mechanisms. Nutrients 8(9)

    Google Scholar 

  • Batra P, Sharma AK (2013) Anti-cancer potential of flavonoids: recent trends and future perspectives. 3 Biotech 3(6):439–459

    Article  PubMed  PubMed Central  Google Scholar 

  • Bieg D, Sypniewski D, Nowak E, Bednarek I (2018) Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch Gynecol Obstet 298(6):1181–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Budach V, Tinhofer I (2019) Novel prognostic clinical factors and biomarkers for outcome prediction in head and neck cancer: a systematic review. Lancet Oncol 20(6):e313–e326

    Article  PubMed  Google Scholar 

  • Chen AY, Chen YC (2013) A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem 138(4):2099–2107

    Article  CAS  PubMed  Google Scholar 

  • Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Prado IM, Helena AF, Uyemura SA, Santos AC, Curti C (2005) The interaction of flavonoids with mitochondria: effects on energetic processes. Chem Biol Interact 152(2–3):67–78

    Article  CAS  PubMed  Google Scholar 

  • Erdogan S, Turkekul K, Serttas R, Erdogan Z (2017) The natural flavonoid apigenin sensitizes human CD44(+) prostate cancer stem cells to cisplatin therapy. Biomed Pharmacother 88:210–217

    Article  CAS  PubMed  Google Scholar 

  • Frey C, Pavani M, Cordano G, Munoz S, Rivera E, Medina J, Morello A, Diego Maya J, Ferreira J (2007) Comparative cytotoxicity of alkyl gallates on mouse tumor cell lines and isolated rat hepatocytes. Comp Biochem Physiol A Mol Integr Physiol 146(4):520–527

    Article  PubMed  Google Scholar 

  • Garg AK, Buchholz TA, Aggarwal BB (2005) Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal 7(11–12):1630–1647

    Article  CAS  PubMed  Google Scholar 

  • Georgiev V, Ananga A, Tsolova V (2014) Recent advances and uses of grape flavonoids as nutraceuticals. Nutrients 6(1):391–415

    Article  PubMed  PubMed Central  Google Scholar 

  • Greenwell M, Rahman PK (2015) Medicinal plants: their use in anticancer treatment. Int J Pharm Sci Res 6(10):4103–4112

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB (2011) Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 1215:150–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han X, Liu CF, Gao N, Zhao J, Xu J (2018) Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells. Biomed Pharmacother 108:809–816

    Article  CAS  PubMed  Google Scholar 

  • Jara JA, Castro-Castillo V, Saavedra-Olavarria J, Peredo L, Pavanni M, Jana F, Letelier ME, Parra E, Becker MI, Morello A, Kemmerling U, Maya JD, Ferreira J (2014) Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice. J Med Chem 57(6):2440–2454

    Article  CAS  PubMed  Google Scholar 

  • Lagoa R, Graziani I, Lopez-Sanchez C, Garcia-Martinez V, Gutierrez-Merino C (2011) Complex I and cytochrome c are molecular targets of flavonoids that inhibit hydrogen peroxide production by mitochondria. Biochim Biophys Acta 1807(12):1562–1572

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Kim JH (2016) Kaempferol inhibits pancreatic cancer cell growth and migration through the blockade of EGFR-related pathway in vitro. PLoS One 11(5):e0155264

    Article  PubMed  PubMed Central  Google Scholar 

  • Li B, Vik SB, Tu Y (2012) Theaflavins inhibit the ATP synthase and the respiratory chain without increasing superoxide production. J Nutr Biochem 23(8):953–960

    Article  CAS  PubMed  Google Scholar 

  • Li X, Lu Y, Lu H, Luo J, Hong Y, Fan Z (2015) AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab. Oncotarget 6(13):11507–11518

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin CW, Chen PN, Chen MK, Yang WE, Tang CH, Yang SF, Hsieh YS (2013) Kaempferol reduces matrix metalloproteinase-2 expression by down-regulating ERK1/2 and the activator protein-1 signaling pathways in oral cancer cells. PLoS One 8(11):e80883

    Article  PubMed  PubMed Central  Google Scholar 

  • Luo H, Rankin GO, Liu L, Daddysman MK, Jiang BH, Chen YC (2009) Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr Cancer 61(4):554–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muratori L, La Salvia A, Sperone P, Di Maio M (2019) Target therapies in recurrent or metastatic head and neck cancer: state of the art and novel perspectives. A systematic review. Crit Rev Oncol Hematol 139:41–52

    Article  PubMed  Google Scholar 

  • Neuzil J, Dong LF, Rohlena J, Truksa J, Ralph SJ (2013) Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion 13(3):199–208

    Article  CAS  PubMed  Google Scholar 

  • Ng CY, Yen H, Hsiao HY, Su SC (2018) Phytochemicals in skin cancer prevention and treatment: an updated review. Int J Mol Sci 19(4)

    Google Scholar 

  • Ojha S, Venkataraman B, Kurdi A, Mahgoub E, Sadek B, Rajesh M (2016) Plant-derived agents for counteracting cisplatin-induced nephrotoxicity. Oxidative Med Cell Longev 2016:4320374

    Google Scholar 

  • Ortega R, Garcia N (2009) The flavonoid quercetin induces changes in mitochondrial permeability by inhibiting adenine nucleotide translocase. J Bioenerg Biomembr 41(1):41–47

    Article  CAS  PubMed  Google Scholar 

  • Peiris-Pages M, Martinez-Outschoorn UE, Pestell RG, Sotgia F, Lisanti MP (2016) Cancer stem cell metabolism. Breast Cancer Res 18(1):55

    Article  PubMed  PubMed Central  Google Scholar 

  • Pendleton KP, Grandis JR (2013) Cisplatin-based chemotherapy options for recurrent and/or metastatic squamous cell Cancer of the head and neck. Clin Med Insights Ther 2013(5)

    Google Scholar 

  • Roberts DJ, Miyamoto S (2015) Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ 22(2):248–257

    Article  CAS  PubMed  Google Scholar 

  • Salvi M, Brunati AM, Clari G, Toninello A (2002) Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore. Biochim Biophys Acta 1556(2–3):187–196

    Article  CAS  PubMed  Google Scholar 

  • Shahid F, Farooqui Z, Khan F (2018) Cisplatin-induced gastrointestinal toxicity: an update on possible mechanisms and on available gastroprotective strategies. Eur J Pharmacol 827:49–57

    Article  CAS  PubMed  Google Scholar 

  • Sun CY, Zhang QY, Zheng GJ, Feng B (2019) Phytochemicals: current strategy to sensitize cancer cells to cisplatin. Biomed Pharmacother 110:518–527

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Ishikawa H, Tanaka A, Mataga I (2011) Heterogeneity of anticancer drug sensitivity in squamous cell carcinoma of the tongue. Hum Cell 24(1):21–29

    Article  CAS  PubMed  Google Scholar 

  • Vafadar A, Shabaninejad Z, Movahedpour A, Fallahi F, Taghavipour M, Ghasemi Y, Akbari M, Shafiee A, Hajighadimi S, Moradizarmehri S, Razi E, Savardashtaki A, Mirzaei H (2020) Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells. Cell Biosci 10:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Valenti D, de Bari L, Manente GA, Rossi L, Mutti L, Moro L, Vacca RA (2013) Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells. Biochim Biophys Acta 1832(12):2085–2096

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Fang X, Ge L, Cao F, Zhao L, Wang Z, Xiao W (2018) Antitumor, antioxidant and anti-inflammatory activities of kaempferol and its corresponding glycosides and the enzymatic preparation of kaempferol. PLoS One 13(5):e0197563

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu XH, Zhao C, Peng Q, Xie P, Liu QH (2017) Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment. Braz J Med Biol Res 50(3):e5396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Liao J, Carter-Cooper BA, Lapidus RG, Cullen KJ, Dan H (2019) Regulation of cisplatin-resistant head and neck squamous cell carcinoma by the SRC/ETS-1 signaling pathway. BMC Cancer 19(1):485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi X, Zuo J, Tan C, Xian S, Luo C, Chen S, Yu L, Luo Y (2016) Kaempferol, a flavonoid compound from Gynura Medica induced apoptosis and growth inhibition in Mcf-7 breast cancer cell. Afr J Tradit Complement Altern Med 13(4):210–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Fondecyt iniciación Grant N°11180533 (JAJ), PRI-ODO 18/003 (JAJ), Fondecyt iniciación Grant N°11160281 (MC), Fondecyt iniciación Grant N°11170962 (IOA).

Conflict of Interest

The authors declare they have no conflict of interests.

Author information

Author notes

  1. Mabel Catalán and Catalina Rodríguez contributed equally with all other contributors.

Authors and Affiliations

  1. Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile

    Mabel Catalán & Diego Rojas

  2. Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile

    Catalina Rodríguez, Javiera Carrasco-Rojas, Alfredo Molina-Berríos, Mario Díaz-Dosque & José A. Jara

  3. Physiopathology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile

    Ivonne Olmedo

Authors
  1. Mabel Catalán
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catalina Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivonne Olmedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Javiera Carrasco-Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diego Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Molina-Berríos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mario Díaz-Dosque
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. José A. Jara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José A. Jara .

Editor information

Editors and Affiliations

  1. (emeritus), Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Kursad Turksen

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Catalán, M. et al. (2020). Kaempferol Induces Cell Death and Sensitizes Human Head and Neck Squamous Cell Carcinoma Cell Lines to Cisplatin. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 12. Advances in Experimental Medicine and Biology(), vol 1326. Springer, Cham. https://doi.org/10.1007/5584_2020_603

Download citation

Publish with us

Policies and ethics

Search

Navigation