Skip to main content
SpringerLink
Log in

Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig.6

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ANOVA:

Analysis of variance

BCIP/NBT:

5-Bromo-4-chloro-3′-indolyphosphate/nitro-blue tetrazolium

DCFDA:

2′,7′-Dichlorofluorescin diacetate

DL:

Dalton’s lymphoma

EDTA:

Ethylenediaminetetraacetic acid

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GLUT1:

Glucose transporter 1

HIF-1α:

Hypoxia-inducible factor 1-alpha

HKII:

Hexokinase II

LDHA:

Lactate dehydrogenase A

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide

PARP:

Poly (ADP-ribose) polymerase

PBS:

Phosphate-buffered saline

PDE5:

Phosphodiesterase 5

PDK1:

Pyruvate dehydrogenase kinase 1

PIPES:

Piperazine-N,N′-bis(2-ethanesulfonic acid)

ROS:

Reactive oxygen species

RPMI:

Roswell park memorial institute medium

RT-PCR:

Reverse-transcription polymerase chain reaction

SDS:

Sodium dodecyl sulphate

References

  1. Niccolini F, Foltynie T, Reis Marques T et al (2015) Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson’s disease. Brain 138:3003–3015. https://doi.org/10.1093/brain/awv219

    Article  PubMed  Google Scholar 

  2. Lorigo M, Oliveira N, Cairrao E (2021) PDE-mediated cyclic nucleotide compartmentation in vascular smooth muscle cells: from basic to a clinical perspective. J Cardiovasc Dev Dis. https://doi.org/10.3390/jcdd9010004

    Article  PubMed  PubMed Central  Google Scholar 

  3. Yang HM, Jin S, Jang H et al (2019) Sildenafil reduces neointimal hyperplasia after angioplasty and inhibits platelet aggregation via activation of cGMP-dependent protein kinase. Sci Rep 9:7769. https://doi.org/10.1038/s41598-019-44190-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kurelic R, Krieg PF, Sonner JK et al (2021) Upregulation of phosphodiesterase 2A augments T cell activation by changing cGMP/cAMP cross-talk. Front Pharmacol 12:748798. https://doi.org/10.3389/fphar.2021.748798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Azevedo MF, Faucz FR, Bimpaki E et al (2014) Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev 35:195–233. https://doi.org/10.1210/er.2013-1053

    Article  CAS  PubMed  Google Scholar 

  6. Barone I, Giordano C, Bonofiglio D, Ando S, Catalano S (2017) Phosphodiesterase type 5 and cancers: progress and challenges. Oncotarget 8:99179–99202. https://doi.org/10.18632/oncotarget.21837

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lin CS, Lin G, Xin ZC, Lue TF (2006) Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 12:3439–3457. https://doi.org/10.2174/138161206778343064

    Article  CAS  PubMed  Google Scholar 

  8. Catalano S, Campana A, Giordano C et al (2016) Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: implications for targeted therapy. Clinical Cancer Res 22:2271–2282. https://doi.org/10.1158/1078-0432.CCR-15-1900

    Article  CAS  Google Scholar 

  9. Li N, Chen X, Zhu B et al (2015) Suppression of beta-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 6:27403–27415. https://doi.org/10.18632/oncotarget.4741

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhang N, Fang Z, Li Q et al (2017) PDE5 overexpression in well-differentiated thyroid carcinomas is associated with lymph node metastasis. Int J Endocrinol 2017:6243932. https://doi.org/10.1155/2017/6243932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu N, Mei L, Fan X et al (2016) Phosphodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway. Cancer Lett 378:38–50. https://doi.org/10.1016/j.canlet.2016.05.010

    Article  CAS  PubMed  Google Scholar 

  12. Black KL, Yin D, Ong JM et al (2008) PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res 1230:290–302. https://doi.org/10.1016/j.brainres.2008.06.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Murata K, Sudo T, Kameyama M et al (2000) Cyclic AMP specific phosphodiesterase activity and colon cancer cell motility. Clin Exp Metastasis 18:599–604. https://doi.org/10.1023/a:1011926116777

    Article  CAS  PubMed  Google Scholar 

  14. Ala M, Mohammad Jafari R, Dehpour AR (2021) Sildenafil beyond erectile dysfunction and pulmonary arterial hypertension: thinking about new indications. Fundam Clin Pharmacol 35:235–259. https://doi.org/10.1111/fcp.12633

    Article  CAS  PubMed  Google Scholar 

  15. Qian CN, Takahashi M, Kahnoski R, Teh BT (2003) Effect of sildenafil citrate on an orthotopic prostate cancer growth and metastasis model. J Urol 170:994–997. https://doi.org/10.1097/01.ju.0000080321.99119.df

    Article  CAS  PubMed  Google Scholar 

  16. Sarfati M, Mateo V, Baudet S et al (2003) Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells. Blood 101:265–269. https://doi.org/10.1182/blood-2002-01-0075

    Article  CAS  PubMed  Google Scholar 

  17. Booth L, Roberts JL, Cruickshanks N et al (2014) Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary cancer cells. Mol Pharmacol 85:408–419. https://doi.org/10.1124/mol.113.090043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Das A, Durrant D, Mitchell C, Dent P, Batra SK, Kukreja RC (2016) Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95. Oncotarget 7:4399–4413. https://doi.org/10.18632/oncotarget.6749

    Article  PubMed  Google Scholar 

  19. Greish K, Fateel M, Abdelghany S et al (2018) Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer. J Drug Target 26:610–615. https://doi.org/10.1080/1061186X.2017.1405427

    Article  CAS  PubMed  Google Scholar 

  20. El-Naa MM, Othman M, Younes S (2016) Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis. Drug Des Devel Ther 10:3661–3672. https://doi.org/10.2147/DDDT.S107490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Das A, Durrant D, Mitchell C et al (2010) Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc Natl Acad Sci USA 107:18202–18207. https://doi.org/10.1073/pnas.1006965107

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ghanbari Movahed Z, Rastegari-Pouyani M, Mohammadi MH, Mansouri K (2019) Cancer cells change their glucose metabolism to overcome increased ROS: one step from cancer cell to cancer stem cell? Biomed Pharmacother 112:108690. https://doi.org/10.1016/j.biopha.2019.108690

    Article  CAS  PubMed  Google Scholar 

  23. Redza-Dutordoir M, Averill-Bates DA (2016) Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 1863:2977–2992. https://doi.org/10.1016/j.bbamcr.2016.09.012

    Article  CAS  PubMed  Google Scholar 

  24. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218. https://doi.org/10.1016/j.tibs.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Warburg O (1956) On the origin of cancer cells. Science 123:309–314. https://doi.org/10.1126/science.123.3191.309

    Article  CAS  PubMed  Google Scholar 

  26. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. https://doi.org/10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Marcucci F, Rumio C (2021) Glycolysis-induced drug resistance in tumors-a response to danger signals? Neoplasia 23:234–245. https://doi.org/10.1016/j.neo.2020.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tchounwou PB, Dasari S, Noubissi FK, Ray P, Kumar S (2021) Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy. J Exp Pharmacol 13:303–328. https://doi.org/10.2147/JEP.S267383

    Article  PubMed  PubMed Central  Google Scholar 

  29. Karasawa T, Steyger PS (2015) An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. Toxicol Lett 237:219–227. https://doi.org/10.1016/j.toxlet.2015.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tang Q, Wang X, Jin H et al (2021) Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies. Eur J Pharm Biopharm 163:60–71. https://doi.org/10.1016/j.ejpb.2021.03.008

    Article  CAS  PubMed  Google Scholar 

  31. Jaiswara PK, Gupta VK, Sonker P et al (2021) Nimbolide induces cell death in T lymphoma cells: Implication of altered apoptosis and glucose metabolism. Environ Toxicol 36:628–641. https://doi.org/10.1002/tox.23067

    Article  CAS  PubMed  Google Scholar 

  32. Gupta VK, Jaiswara PK, Sonker P, Rawat SG, Tiwari RK, Kumar A (2020) Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism. Apoptosis 25:135–150. https://doi.org/10.1007/s10495-019-01585-1

    Article  CAS  PubMed  Google Scholar 

  33. Marbach EP, Weil MH (1967) Rapid enzymatic measurement of blood lactate and pyruvate. Use and significance of metaphosphoric acid as a common precipitant. Clin Chem 13:314–325

    Article  CAS  Google Scholar 

  34. Mei XL, Yang Y, Zhang YJ et al (2015) Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo. Am J Cancer Res 5:3311–3324

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sponziello M, Verrienti A, Rosignolo F et al (2015) PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells. Endocrine 50:434–441. https://doi.org/10.1007/s12020-015-0586-x

    Article  CAS  PubMed  Google Scholar 

  36. Klutzny S, Anurin A, Nicke B et al (2018) PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling. Cell Death Dis 9:192. https://doi.org/10.1038/s41419-017-0202-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Domvri K, Zarogoulidis K, Zogas N et al (2017) Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer. J Cancer 8:3648–3656. https://doi.org/10.7150/jca.21783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li Q, Shu Y (2014) Pharmacological modulation of cytotoxicity and cellular uptake of anti-cancer drugs by PDE5 inhibitors in lung cancer cells. Pharm Res 31:86–96. https://doi.org/10.1007/s11095-013-1134-0

    Article  CAS  PubMed  Google Scholar 

  39. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. https://doi.org/10.1016/j.ejphar.2014.07.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kleih M, Bopple K, Dong M et al (2019) Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis 10:851. https://doi.org/10.1038/s41419-019-2081-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tavallai M, Hamed HA, Roberts JL et al (2015) Nexavar/Stivarga and viagra interact to kill tumor cells. J Cell Physiol 230:2281–2298. https://doi.org/10.1002/jcp.24961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Beloueche-Babari M, Wantuch S, Casals Galobart T et al (2017) MCT1 Inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy. Can Res 77:5913–5924. https://doi.org/10.1158/0008-5472.CAN-16-2686

    Article  CAS  Google Scholar 

  43. Kittipongdaja W, Wu X, Garner J et al (2015) Rapamycin suppresses tumor growth and alters the metabolic phenotype in T-cell lymphoma. J Invest Dermatol 135:2301–2308. https://doi.org/10.1038/jid.2015.153

    Article  CAS  PubMed  Google Scholar 

  44. Kumar A, Kant S, Singh SM (2012) Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem Biol Interact 199:29–37. https://doi.org/10.1016/j.cbi.2012.06.005

    Article  CAS  PubMed  Google Scholar 

  45. Kumar A, Kant S, Singh SM (2013) Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: a role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation. Toxicol Appl Pharmacol 273:196–208. https://doi.org/10.1016/j.taap.2013.09.005

    Article  CAS  PubMed  Google Scholar 

  46. Di X, Gennings C, Bear HD et al (2010) Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat 124:349–360. https://doi.org/10.1007/s10549-010-0765-7

    Article  CAS  PubMed  Google Scholar 

  47. Hassanvand F, Mohammadi T, Ayoubzadeh N et al (2020) Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells. J Cancer Res Ther 16:1412–1418. https://doi.org/10.4103/jcrt.JCRT_675_19

    Article  CAS  PubMed  Google Scholar 

  48. Gao JL, Chen YG (2015) Natural compounds regulate glycolysis in hypoxic tumor microenvironment. Biomed Res Int 2015:354143. https://doi.org/10.1155/2015/354143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ikeda H, Kakeya H (2021) Targeting hypoxia-inducible factor 1 (HIF-1) signaling with natural products toward cancer chemotherapy. J Antibiot (Tokyo) 74:687–695. https://doi.org/10.1038/s41429-021-00451-0

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thankfully acknowledge fellowship support to Shiv Govind Rawat (Award No. 09/013(0772/2018-EMR-I)), Pradip Kumar Jaiswara (Award No. 1002/(SC)(CSIR-UGC NET DEC. 2016), and Vishal Kumar Gupta (Award No. 1044/(CSIR-UGC NET JUNE 2019) from CSIR, New Delhi. The fellowship supports to Rajan Kumar Tiwari (Award No. R/Dev/IX-Sch.(SRF-JRF-CAS-Zoology)/75159) from University Grants Commission-Career Advancement Scheme (UGC-CAS) is highly acknowledged. Funding from the Indian Council of Medical Research, New Delhi, India (Grant Number: IRIS ID-2021-13098) is highly acknowledged. The authors also acknowledge UGC-CAS and the Department of Science & Technology-Fund for Improvement of S&T Infrastructure (DST-FIST) program to the Department of Zoology, Banaras Hindu University, India. The authors thank Dr. Subhash Chandra Gupta (Department of Biochemistry, Banaras Hindu University, Varanasi) for providing the PARP antibody.

Funding

This work was supported by the Indian Council of Medical Research, New Delhi, India (Grant Number: IRIS ID-2021–13098).

Author information

Authors and Affiliations

  1. Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Shiv Govind Rawat, Rajan Kumar Tiwari, Pradip Kumar Jaiswara, Vishal Kumar Gupta, Pratishtha Sonker & Ajay Kumar

  2. Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

    Naveen Kumar Vishvakarma

  3. Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India

    Santosh Kumar

  4. Amity Institute of Biotechnology, Amity University, Amity Education Valley, Gurgaon, Haryana, India

    Chandramani Pathak

  5. Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, 221005, Varanasi, India

    Vibhav Gautam

Authors
  1. Shiv Govind Rawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajan Kumar Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pradip Kumar Jaiswara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vishal Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pratishtha Sonker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naveen Kumar Vishvakarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Santosh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chandramani Pathak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vibhav Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ajay Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The research work presented in this manuscript is part of the PhD thesis of SGR. The experiments of this investigation were designed by AK and SGR. SGR has performed the entire experiments of the study. The manuscript was written by AK, SGR, NKV, SK, CP, and VG. SGR, RKT, PKJ, VKG, and PS prepared reagents. The experimental data were analyzed by AK, SGR, RKT, PKJ, VKG, PS, NKV, SK, CP, and VG. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Ajay Kumar.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 330 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rawat, S.G., Tiwari, R.K., Jaiswara, P.K. et al. Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism. Apoptosis 27, 606–618 (2022). https://doi.org/10.1007/s10495-022-01741-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-022-01741-0

Keywords

Search

Navigation