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Anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8–5 cells

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Abstract

Background

The demand for environmentally friendly and cost-effective plant-based products for the development of cancer therapeutics has been increasing. Yohimbine (α2-adrenergic receptor antagonist) is a stimulant and aphrodisiac used to improve erectile dysfunction. In this study, we aimed to evaluate the anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8–5 cells using different biomolecular techniques.

Methods

We estimated the anticancer efficacy of yohimbine using different assays, such as MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell cytotoxicity, cell morphology, cell apoptosis, reactive oxygen species (ROS) formation, and modulation in the mitochondrial membrane potential (MMP).

Results

Yohimbine showed a dose-dependent increase in cytotoxicity with a 50% inhibitory concentration (IC50) of 44 µM against KB-ChR-8–5 cancer cell lines. Yohimbine treatment at 40 µM and 50 µM resulted in a considerable change in cell morphology, including shrinkage, detachment, membrane blebbing, and deformed shape. Moreover, at the dose of IC50 and above, a significant induction was observed in the generation of ROS and depolarization of MMP. The possible mechanisms of action of yohimbine underlying the dose-dependent increase in cytotoxicity may be due to the induction of apoptosis, ROS generation, and modulation of MMP.

Conclusion

Overall, yohimbine showed a significant anticancer potential against drug-resistant oral cancer KB-ChR-8–5 cells. Our study suggests that besides being an aphrodisiac, yohimbine can be used as a drug repurposing agent. However, more research is required in different in vitro and in vivo models to confirm the feasibility of yohimbine in clinics.

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References

  1. Nandi S, Dey R, Samadder A, Saxena A, Saxena AK (2022) Natural Sourced inhibitors of EGFR, PDGFR, FGFR and VEGFRMediated signaling pathways as potential anticancer agents. Curr Med Chem 29(2):212–234. https://doi.org/10.2174/0929867328666210303101345

    Article  CAS  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  3. Duarte D, Vale N (2022) Evaluation of synergism in drug combinations and reference models for future orientations in oncology. Curr Res Pharmacol Drug Discov 3:100110. https://doi.org/10.1016/j.crphar.2022.100110

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mishra A, Dey S (2019) Molecular docking studies of a cyclic octapeptide-cyclosaplin from sandalwood. Biomolecules 9(11):740. https://doi.org/10.3390/biom9110740

    Article  CAS  PubMed Central  Google Scholar 

  5. Babich O, Larina V, Ivanova S, Tarasov A, Povydysh M, Orlova A et al (2022) Phytotherapeutic approaches to the prevention of age-related changes and the extension of active longevity. Molecules 27(7):2276. https://doi.org/10.3390/molecules27072276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang H, Poznik M, Tang S, Xue P, Du L, Liu C et al (2021) Synthesis of conformationally liberated yohimbine analogues and evaluation of cytotoxic activity. ACS Omega 6(29):19291–19303. https://doi.org/10.1021/acsomega.1c02784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jabir NR, Firoz CK, Zughaibi TA, Alsaadi MA, Abuzenadah AM, Al-Asmari AI et al (2022) Pharmacological insights of yohimbine: a literature perspective. Annal Med

  8. Obreshkova D, Tsvetkova D (2016) Validation of HPLC method with UV-detection for determination of yohimbine containing products. Pharmacia 63:3–9

    Google Scholar 

  9. Hai-Bo L, Yong P, Lu-qi H, Jun X, Pei-Gen X (2013) Mechanism of selective inhibition of yohimbine and Its derivatives in adrenoceptor α2 subtypes. J Chem 2013:e783058. https://doi.org/10.1155/2013/783058

    Article  CAS  Google Scholar 

  10. Abuzenadah A, Al-Sayes F, Alam S, Hoque M, Karim S, Hussain I et al (2022) Identification of potential poly(ADP-ribose)polymerase-1 inhibitors derived from Rauwolfia serpentina: possible implication in cancer therapy. Evid Based Complemt Alter Med 2022:3787162. https://doi.org/10.1155/2022/

    Article  Google Scholar 

  11. Abuzenadah A, Al-Sayes F, Alam S, Hoque M, Karim S, Hussain I et al (2022) Elucidating anti-angiogenic potential of Rauwolfia serpentina: VEGFR-2 targeting based molecular docking study. Evid Based Complement Alter Med 2022:6224666. https://doi.org/10.1155/2021/

    Article  Google Scholar 

  12. Farouk M, Abd El-Aziz L, El-Gindy AE, Shokry E (2011) Validated methods for determination of yohimbine hydrochloride in the presence of its degradation products. Bull Faculty Pharm Cairo Univ 49(2):67–79. https://doi.org/10.1016/j.bfopcu.2011.09.002

    Article  CAS  Google Scholar 

  13. Miller ER, Hovey MT, Scheidt KA (2020) A concise, enantioselective approach for the synthesis of yohimbine alkaloids. J Am Chem Soc 142(5):2187–2192. https://doi.org/10.1021/jacs.9b12319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tam SW, Worcel M, Wyllie M (2001) Yohimbine: a clinical review. Pharmacol Ther 91(3):215–243. https://doi.org/10.1016/s0163-7258(01)00156-5

    Article  CAS  PubMed  Google Scholar 

  15. Senbel AM, Mostafa T (2008) Yohimbine enhances the effect of sildenafil on erectile process in rats. Int J Impot Res 20(4):409–417. https://doi.org/10.1038/sj.ijir.3901630

    Article  CAS  PubMed  Google Scholar 

  16. Coelho M, Moz M, Correia G, Teixeira A, Medeiros R, Ribeiro L (2015) Antiproliferative effects of β-blockers on human colorectal cancer cells. Oncol Rep 33(5):2513–2520. https://doi.org/10.3892/or.2015.3874

    Article  CAS  PubMed  Google Scholar 

  17. Barbieri A, Bimonte S, Palma G, Luciano A, Rea D, Giudice A et al (2015) The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. Int J Oncol 47(2):527–534. https://doi.org/10.3892/ijo.2015.3038

    Article  CAS  PubMed  Google Scholar 

  18. Lin Q, Wang F, Yang R, Zheng X, Gao H, Zhang P (2013) Effect of chronic restraint stress on human colorectal carcinoma growth in mice. Plos ONE 8(4):e61435. https://doi.org/10.1371/journal.pone.0061435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Millan MJ, Newman-Tancredi A, Audinot V, Cussac D, Lejeune F, Nicolas JP et al (2000) Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Synapse. 35(2):79–95

    Article  CAS  Google Scholar 

  20. Paciaroni NG, Norwood VM, Ratnayake R, Luesch H, Huigens RW (2020) Yohimbine as a starting point to access diverse natural product-like agents with re-programmed activities against cancer-relevant GPCR targets. Bioorg Med Chem 28(14):115546. https://doi.org/10.1016/j.bmc.2020.115546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Alhosaini K, Azhar A, Alonazi A, Al-Zoghaibi F (2021) GPCRs: The most promiscuous druggable receptor of the mankind. Saudi Pharma J 29(6):539–551. https://doi.org/10.1016/j.jsps.2021.04.015

    Article  CAS  Google Scholar 

  22. Amaro F, Silva D, Reguengo H, Oliveira JC, Quintas C, Vale N et al (2020) β-Adrenoceptor activation in breast MCF-10A cells induces a pattern of catecholamine production similar to that of tumorigenic MCF-7 cells. Int J Mol Sci 21(21):7968. https://doi.org/10.3390/ijms21217968

    Article  CAS  PubMed Central  Google Scholar 

  23. Dal Monte M, Calvani M, Cammalleri M, Favre C, Filippi L, Bagnoli P (2019) β-Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3-adrenoceptors. Br J Pharmacol 176(14):2496–2508. https://doi.org/10.1111/bph.14552

    Article  CAS  Google Scholar 

  24. Yazawa T, Kaira K, Shimizu K, Shimizu A, Mori K, Nagashima T et al (2016) Prognostic significance of β2-adrenergic receptor expression in non-small cell lung cancer. Am J Transl Res 8(11):5059–5070

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Dai S, Mo Y, Wang Y, Xiang B, Liao Q, Zhou M et al (2020) Chronic stress promotes cancer development. Front Oncol. https://doi.org/10.3389/fonc.2020.01492

    Article  PubMed  PubMed Central  Google Scholar 

  26. Baskić D, Popović S, Ristić P, Arsenijević NN (2006) Analysis of cycloheximide-induced apoptosis in human leukocytes: fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol Int 30(11):924–932. https://doi.org/10.1016/j.cellbi.2006.06.016

    Article  CAS  PubMed  Google Scholar 

  27. Alharthy SA, Tabrez S, Mirza AA, Zughaibi TA, Firoz CK, Dutta M (2022) Sugiol suppresses the proliferation of human U87 glioma cells via induction of apoptosis and cell cycle arrest. Evid Based Complement Alter Med 2022:e7658899. https://doi.org/10.1155/2022/7658899

    Article  Google Scholar 

  28. Tabrez S, Hoque M, Suhail M, Khan MI, Zughaibi TA, Khan AU (2022) Identification of anticancer bioactive compounds derived from Ficus sp by targeting Poly[ADP-ribose]polymerase 1 (PARP-1). J King Saud Univ Sci 34(5):102079. https://doi.org/10.1016/j.jksus.2022.102079

    Article  Google Scholar 

  29. Tabrez S, Khan AU, Mirza AA, Suhail M, Jabir NR, Zughaibi TA et al (2022) Biosynthesis of copper oxide nanoparticles and its therapeutic efficacy against colon cancer. Nanotechnol Rev 11(1):1322–1331. https://doi.org/10.1515/ntrev-2022-0081

    Article  CAS  Google Scholar 

  30. Prasathkumar M, Anisha S, Dhrisya C, Becky R, Sadhasivam S (2021) Therapeutic and pharmacological efficacy of selective Indian medicinal plants – a review. Phytomedicine Plus 1(2):100029. https://doi.org/10.1016/j.phyplu.2021.100029

    Article  Google Scholar 

  31. Zughaibi TA, Suhail M, Tarique M, Tabrez S (2021) Targeting PI3K/Akt/mTOR pathway by different flavonoids: a cancer chemopreventive approach. Int J Mol Sci 22(22):12455. https://doi.org/10.3390/ijms222212455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tabrez S, Khan A, Suhail M, Khan M, Zughaibi T, Hoque M (2022) Biosynthesis of ZnO NPs from pumpkin seeds extract and elucidation of its anticancer activity against breast cancer. Nanotechnol Rev 11:2714

    Article  CAS  Google Scholar 

  33. Tabrez S, Zughaibi T, Hoque M, Suhail M, Khan M, Khan A (2022) Targeting glutaminase by natural compounds: structure-based virtual screening and molecular dynamics simulation approach to suppress cancer progression. Molecules 27:5047

    Article  Google Scholar 

  34. Gowd V, Ahmad A, Tarique M, Suhail M, Zughaibi TA, Tabrez S et al (2022) Advancement of cancer immunotherapy using nanoparticles-based nanomedicine. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2022.03.026

    Article  PubMed  Google Scholar 

  35. Muhammad N, Usmani D, Tarique M, Naz H, Ashraf M, Raliya R et al (2022) The role of natural products and their multitargeted approach to treat solid cancer. Cells 11(14):2209. https://doi.org/10.3390/cells11142209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gérard C, Goldbeter A (2014) The balance between cell cycle arrest and cell proliferation: control by the extracellular matrix and by contact inhibition. Interf Focus 4(3):20130075. https://doi.org/10.1098/rsfs.2013.0075

    Article  Google Scholar 

  37. Stefanowicz-Hajduk J, Hering A, Gucwa M, Sztormowska-Achranowicz K, Kowalczyk M, Soluch A et al (2022) An in vitro anticancer, antioxidant, and phytochemical study on water extract of kalanchoe daigremontiana Raym-Hamet and H. Perrier. Molecules. 27(7):2280. https://doi.org/10.3390/molecules27072280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alserihi RF, Mohammed MRS, Kaleem M, Khan MI, Sechi M, Sanna V et al (2022) Development of (−)-epigallocatechin-3-gallate-loaded folate receptor-targeted nanoparticles for prostate cancer treatment. Nanotechnol Rev 11(1):298–311. https://doi.org/10.1515/ntrev-2022-0013

    Article  CAS  Google Scholar 

  39. Tabrez S, Jabir NR, Adhami VM, Khan MI, Moulay M, Kamal MA et al (2020) Nanoencapsulated dietary polyphenols for cancer prevention and treatment: successes and challenges. Nanomed (Lond) 15(11):1147–62. https://doi.org/10.2217/nnm-2019-0398

    Article  CAS  Google Scholar 

  40. Lam VQ, Anh LH, Quan NV, Xuan TD, Hanamura I, Uchino K et al (2022) Cytotoxicity of callerya speciosa fractions against myeloma and lymphoma cell lines. Molecules 27(7):2322. https://doi.org/10.3390/molecules27072322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zughaibi TA, Mirza AA, Suhail M, Jabir NR, Zaidi SK, Wasi S et al (2022) Evaluation of anticancer potential of biogenic copper oxide nanoparticles (CuO NPs) against breast cancer. J Nanomater 2022:e5326355. https://doi.org/10.1155/2022/5326355

    Article  CAS  Google Scholar 

  42. Islam BU, Khan MS, Husain FM, Rehman MT, Zughaibi TA, Abuzenadah AM et al (2021) mTOR Targeted cancer chemoprevention by flavonoids. Curr Med Chem 28(39):8068–8082. https://doi.org/10.2174/0929867327666201109122025

    Article  Google Scholar 

  43. Shen S-G, Zhang D, Hu H-T, Li J-H, Wang Z, Ma Q-Y (2008) Effects of alpha-adrenoreceptor antagonists on apoptosis and proliferation of pancreatic cancer cells in vitro. World J Gastroenterol 14(15):2358–2363. https://doi.org/10.3748/wjg.14.2358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhan G, Miao R, Zhang F, Wang X, Zhang X, Guo Z (2020) Cytotoxic yohimbine-type alkaloids from the leaves of Rauvolfia vomitoria. Chem Biodivers 17(12):e2000647. https://doi.org/10.1002/cbdv.202000647

    Article  CAS  PubMed  Google Scholar 

  45. Liu K, Liu P-c, Liu R, Wu X (2015) Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry. Med Sci Monit Basic Res 21:15–20. https://doi.org/10.12659/MSMBR.893327

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kc B, Paudel SN, Rayamajhi S, Karna D, Adhikari S, Shrestha BG et al (2016) Enhanced preferential cytotoxicity through surface modification: synthesis, characterization and comparative in vitro evaluation of TritonX-100 modified and unmodified zinc oxide nanoparticles in human breast cancer cell (MDA-MB-231). Chem Cent J 10:16. https://doi.org/10.1186/s13065-016-0162-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ribble D, Goldstein NB, Norris DA, Shellman YG (2005) A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol 5:12. https://doi.org/10.1186/1472-6750-5-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gherghi IC, Girousi ST, Voulgaropoulos AN, Tzimou-Tsitouridou R (2003) Study of interactions between DNA-ethidium bromide (EB) and DNA-acridine orange (AO), in solution, using hanging mercury drop electrode (HMDE). Talanta 61(2):103–112. https://doi.org/10.1016/S0039-9140(03)00238-8

    Article  CAS  PubMed  Google Scholar 

  49. Carneiro BA, El-Deiry WS (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 17(7):395–417. https://doi.org/10.1038/s41571-020-0341-y

    Article  PubMed  PubMed Central  Google Scholar 

  50. Castillo Ferrer C, Berthenet K, Ichim G (2021) Apoptosis – fueling the oncogenic fire. FEBS J 288(15):4445–4463. https://doi.org/10.1111/febs.15624

    Article  CAS  PubMed  Google Scholar 

  51. Delierneux C, Kouba S, Shanmughapriya S, Potier-Cartereau M, Trebak M, Hempel N (2020) Mitochondrial calcium regulation of redox signaling in cancer. Cells 9(2):E432. https://doi.org/10.3390/cells9020432

    Article  CAS  PubMed  Google Scholar 

  52. Jaudan A, Sharma S, Malek SNA, Dixit A (2018) Induction of apoptosis by pinostrobin in human cervical cancer cells: possible mechanism of action. Plos ONE. 13(2):e0191523. https://doi.org/10.1371/journal.pone.0191523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zou P, Zhang J, Xia Y, Kanchana K, Guo G, Chen W et al (2015) ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. Oncotarget 6(8):5860–5876. https://doi.org/10.18632/oncotarget.3333

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

MSK acknowledges the generous support from the Research Supporting Project (RSP-2021/352) by the King Saud University, Riyadh, Kingdom of Saudi Arabia.

Funding

Funding was provided by King Saud University.

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Authors and Affiliations

  1. Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, 613403, India

    Nasimudeen R. Jabir & Bakrudeen Ali Ahmed

  2. Department of Biochemistry, College of Sciences, King Saud University, Riyadh, 11451, Saudi Arabia

    Mohd Shahnawaz Khan & Nouf Omar Alafaleq

  3. Department of Medicine, University of Missouri, Columbia, MO, 65201, USA

    Huma Naz

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Contributions

NRJ, MSK, and NOA performed the experiments and made first draft of the article. HN and BAA were involved in the analysis of the data and guidance throughout the work. All authors reviewed the final draft of manuscript.

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Correspondence to Mohd Shahnawaz Khan or Bakrudeen Ali Ahmed.

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Jabir, N.R., Khan, M.S., Alafaleq, N.O. et al. Anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8–5 cells. Mol Biol Rep 49, 9565–9573 (2022). https://doi.org/10.1007/s11033-022-07847-7

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