Effect of zoledronic acid on biological characteristics of cervical cancer cells

Ling Qin, Xuqun Ding

Abstract

Cervical cancer (CC) is a malignant tumor in females characterized by high incidence and mortality rates, often resulting in a poor prognosis for patients. Zoledronic acid (ZA), a third-generation bisphosphonate, exhibits anti-tumor properties across various types of tumors. To further understand the effect of ZA in the treatment of CC, this article included two kinds of human CC cells (CCCs) as the research object, examining the impact of varying levels of ZA on the cells’ biological properties. Hela and Siha were cultivated and exposed to ZA at 0, 50, 100, and 200 μM, and the changes of cell proliferation, clone formation, migration, and invasion characteristics were detected. Cell RNA was extracted to detect epithelial-mesenchymal transition (EMT) and the relative expression (RE) of AKT/GSK3β/β-catenin (β-cat) pathway related proteins. The results show that as against 0 μM, the proliferation rate, clone formation cell number, migration distance, and invasive cell number of Hela and Siha were markedly reduced, while Ecadherin (E-cad) was markedly enhanced. N-cadherin (N-cad), vimentin (Vim), p-AKT, p-GSK3β, and β-cat were markedly decreased at 50, 100, and 200 μM ZA; With the increase of ZA concentration, the biological characteristics and protein expression levels of Hela and Siha changed more markedly, showing concentration dependent characteristics (P < 0.05). It was concluded that ZA can influence the malignant biological activities of CCCs.

Full Text:

PDF

References

Rose MM, Dhamodharan S, Revathidevi S,

Chakkarappan SR, Jagadeesan MG, Subbiah S,

Nakaoka H, Inoue I, Murugan AK and

Munirajan AK. High incidence of PI3K pathway

gene mutations in South Indian cervical cancers.

Cancer Genet. 2022;264-265:100-108.

Bhattacharjee R, Das SS, Biswal SS, Nath A, Das D,

Basu A, Malik S, Kumar L, Kar S, Singh SK,

Upadhye VJ, Iqbal D, Almojam S,

Roychoudhury S, Ojha S, Ruokolainen J, Jha

NK and Kesari KK. Mechanistic role of HPVassociated early proteins in cervical cancer:

Molecular pathways and targeted therapeutic

strategies. Crit Rev Oncol Hematol.

;174:103675.

Mayadev JS, Ke G, Mahantshetty U, Pereira MD,

Tarnawski R and Toita T. Global challenges of

radiotherapy for the treatment of locally

advanced cervical cancer. Int J Gynecol Cancer.

;32(3):436-445.

Schubert M, Bauerschlag DO, Muallem MZ, Maass N

and Alkatout I. Challenges in the Diagnosis and

Individualized Treatment of Cervical Cancer.

Medicina (Kaunas). 2023;59(5):925.

Jere SW, Houreld NN and Abrahamse H. Role of the

PI3K/AKT (mTOR and GSK3β) signalling

pathway and photobiomodulation in diabetic

wound healing. Cytokine Growth Factor Rev.

;50:52-59.

Zhang Y and Wang X. Targeting the Wnt/β-catenin

signaling pathway in cancer. J Hematol Oncol.

;13(1):165.

Liu C, He P, Guo Y, Tian Q, Wang J, Wang G, Zhang

Z and Li M. Taurine attenuates neuronal

ferroptosis by regulating

GABAB/AKT/GSK3β/β-catenin pathway after

subarachnoid hemorrhage. Free Radic Biol Med.

;193(Pt 2):795-807.

Zhao SJ, Kong FQ, Jie J, Li Q, Liu H, Xu AD, Yang

YQ, Jiang B, Wang DD, Zhou ZQ, Tang PY,

Chen J, Wang Q, Zhou Z, Chen Q, Yin GY,

Zhang HW and Fan J. Macrophage MSR1

promotes BMSC osteogenic differentiation and

M2-like polarization by activating

PI3K/AKT/GSK3β/β-catenin pathway.

Theranostics. 2020;10(1):17-35.

Yu H, Zhou L, Loong JHC, Lam KH, Wong TL, Ng

KY, Tong M, Ma VWS, Wang Y, Zhang X, Lee

TK, Yun JP, Yu J and Ma S. SERPINA12

promotes the tumorigenic capacity of HCC stem

cells through hyperactivation of AKT/β-catenin

signaling. Hepatology. 2023;78(6):1711-1726.

Zhang Y, Li JH, Yuan QG and Yang WB. Restraint of

FAM60A has a cancer-inhibiting role in

pancreatic carcinoma via the effects on the

Akt/GSK-3β/β-catenin signaling pathway.

Environ Toxicol. 2022;37(6):1432-1444.

Ishikawa T. Differences between zoledronic acid and

denosumab for breast cancer treatment. J Bone

Miner Metab. 2023;41(3):301-306.

Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm

A, Bornstein MM and Molinero-Mourelle P.

Medication-related osteonecrosis of the jaws

(MRONJ) in cancer patients treated with

denosumab VS. zoledronic acid: A systematic

review and meta-analysis. Med Oral Patol Oral

Cir Bucal. 2020;25(3):e326-e336.

Wang S, Huang M, Chen M, Sun Z, Jiao Y, Ye G, Pan

J, Ye W, Zhao J and Zhang D. Zoledronic acid

and thymosin α1 elicit antitumor immunity

against prostate cancer by enhancing tumor

inflammation and cytotoxic T cells. J

Immunother Cancer. 2023;11(6):e006381.

Huang SY, Yoon SS, Shimizu K, Chng WJ, Chang CS,

Wong RS, Gao S, Wang Y, Gordon SW,

Glennane A and Min CK. Denosumab Versus

Zoledronic Acid in Bone Disease Treatment of

Newly Diagnosed Multiple Myeloma: An

International, Double-Blind, Randomized

Controlled Phase 3 Study-Asian Subgroup

Analysis. Adv Ther. 2020;37(7):3404-3416.

Liu M, Qian S, Wu J, Xiao J and Zeng X. The effects

of neoadjuvant zoledronic acid in breast cancer

patients: A meta-analysis of randomized

controlled trials. Asian J Surg.

;46(10):4124-4130.

Mahapatra BR, Muraleedharan A, Badajena A, Das

Majumdar SK and Haroon K M N. Cutaneous

Metastasis in a Treated Case of Cervical Cancer

With Extraordinary Response to Chemotherapy:

A Case Report of a Rare Event and Review of

the Literature. Cureus. 2023;15(2):e35083.

Zhang T, Zhuang L, Muaibati M, Wang D, Abasi A,

Tong Q, Ma D, Jin L and Huang X. Identification

of cervical cancer stem cells using single-cell

transcriptomes of normal cervix, cervical

premalignant lesions, and cervical cancer.

EBioMedicine. 2023;92:104612.

Tian Q, Liu X, Li A, Wu H, Xie Y, Zhang H, Wu F,

Chen Y, Bai C and Zhang X. LINC01936

inhibits the proliferation and metastasis of lung

squamous cell carcinoma probably by EMT

signaling and immune infiltration. PeerJ.

;11:e16447.

Pons M and Beyer M. Colony Formation Assay to Test

the Impact of HDACi on Leukemic Cells.

Methods Mol Biol. 2023;2589:17-25.

Freitas JT, Jozic I and Bedogni B. Wound Healing

Assay for Melanoma Cell Migration. Methods

Mol Biol. 2021;2265:65-71.

Ghose R, Rice AJ, Cortes E, Ghose U, Lachowski D

and Del Rio Hernandez A. Implementation of a

basement membrane invasion assay using

mesenteric tissue. Methods Cell Biol.

;157:99-122.

Taylor SC, Berkelman T, Yadav G and Hammond M.

A defined methodology for reliable

quantification of Western blot data. Mol

Biotechnol. 2013;55(3):217-26.

Zheng Y, Wang PP, Fu Y, Chen YY and Ding ZY.

Zoledronic acid enhances the efficacy of

immunotherapy in non-small cell lung cancer.

Int Immunopharmacol. 2022;110:109030.

Lin JF, Lin YC, Lin YH, Tsai TF, Chou KY, Chen HE

and Hwang TI. Zoledronic acid induces

autophagic cell death in human prostate cancer

cells. J Urol. 2011;185(4):1490-6.

Adibi R, Moein S, Gheisari Y. Zoledronic acid targets

chemo-resistant polyploid giant cancer cells. Sci

Rep. 2023;13(1):419.

Liu H and Li Y. Potential roles of Cornichon Family

AMPA Receptor Auxiliary Protein 4 (CNIH4) in

head and neck squamous cell carcinoma. Cancer

Biomark. 2022;35(4):439-450.

Nishimura T, Kakiuchi N, Yoshida K, Sakurai T,

Kataoka TR, Kondoh E, Chigusa Y, Kawai M,

Sawada M, Inoue T, Takeuchi Y, Maeda H, Baba

S, Shiozawa Y, Saiki R, Nakagawa MM, Nannya

Y, Ochi Y, Hirano T, Nakagawa T, InagakiKawata Y, Aoki K, Hirata M, Nanki K, Matano

M, Saito M, Suzuki E, Takada M, Kawashima

M, Kawaguchi K, Chiba K, Shiraishi Y, Takita

J, Miyano S, Mandai M, Sato T, Takeuchi K,

Haga H, Toi M and Ogawa S. Evolutionary

histories of breast cancer and related clones.

Nature. 2023;620(7974):607-614.

Liu H, Dilger JP and Lin J. Lidocaine Suppresses

Viability and Migration of Human Breast Cancer

Cells: TRPM7 as a Target for Some Breast

Cancer Cell Lines. Cancers (Basel).

;13(2):234.

Chitsike L and Duerksen-Hughes P. The Potential of

Immune Checkpoint Blockade in Cervical

Cancer: Can Combinatorial Regimens Maximize

Response? A Review of the Literature. Curr

Treat Options Oncol. 2020;21(12):95.

Leung KH, Rowe SP, Sadaghiani MS, Leal JP, Mena

E, Choyke PL, Du Y and Pomper MG. Deep Semisupervised Transfer Learning for Fully

Automated Whole-Body Tumor Quantification

and Prognosis of Cancer on PET/CT. J Nucl

Med. 2024;65(4):643-650.

Cavinato L, Gozzi N, Sollini M, Kirienko M, CarloStella C, Rusconi C, Chiti A and Ieva F.

Explainable domain transfer of distant

supervised cancer subtyping model via imagingbased rules extraction. Artif Intell Med.

;138:102522.

Xu J, Pan Q and Ju W. Ras inhibition by zoledronic acid

effectively sensitizes cervical cancer to

chemotherapy. Anticancer Drugs.

;30(8):821-827.

Wang IT, Chou SC and Lin YC. Zoledronic acid

induces apoptosis and autophagy in cervical

cancer cells. Tumour Biol. 2014;35(12):11913-

Rubtsova SN, Zhitnyak IY and Gloushankova NA.

Dual role of E-cadherin in cancer cells. Tissue

Barriers. 2022;10(4):2005420.

Grasset EM, Dunworth M, Sharma G, Loth M,

Tandurella J, Cimino-Mathews A, Gentz M,

Bracht S, Haynes M, Fertig EJ and Ewald AJ.

Triple-negative breast cancer metastasis

involves complex epithelial-mesenchymal

transition dynamics and requires vimentin. Sci

Transl Med. 2022;14(656):eabn7571.

Wu S, Li X, Chai H, Feng L, Li W and Li H.

Downregulation of N-myc Interactor Promotes

Cervical Cancer Cells Growth by Activating

Stat3 Signaling. Cell Biochem Biophys.

;79(1):103-111.

Kim L, Park SA, Park H, Kim H and Heo TH.

Bazedoxifene, a GP130 Inhibitor, Modulates

EMT Signaling and Exhibits Antitumor Effects

in HPV-Positive Cervical Cancer. Int J Mol Sci.

;22(16):8693.

Huang W, Wen F, Yang P, Li Y, Li Q and Shu P. Yiqi-hua-yu-jie-du decoction induces ferroptosis in

cisplatin-resistant gastric cancer via the

AKT/GSK3β/NRF2/GPX4 axis. Phytomedicine.

; 123:155220.

Zhong J, Yuan C, Liu L, Du Y, Hui Y, Chen Z, Diao C,

Yang R, Liu G and Liu X. PCMT1 regulates the

migration, invasion, and apoptosis of prostate

cancer through modulating the PI3K/AKT/GSK3β pathway. Aging (Albany NY).

;15(20):11654-11671.

Kim EH, Kim MS, Lee KH, Koh JS, Jung WG, Kong

CB. Zoledronic acid is an effective

radiosensitizer in the treatment of osteosarcoma.

Oncotarget. 2016;7(43):70869-70880.

Peng Y, Qiu L, Xu D, Zhang L, Yu H, Ding Y, Deng L

and Lin J. M4IDP, a zoledronic acid derivative,

induces G1 arrest, apoptosis and autophagy in

HCT116 colon carcinoma cells via blocking

PI3K/Akt/mTOR pathway. Life Sci. 2017;

:63-72.

Wang L, Liu Y, Zhou Y, Wang J, Tu L, Sun Z, Wang

X and Luo F. Zoledronic acid inhibits the growth

of cancer stem cell derived from cervical cancer

cell by attenuating their stemness phenotype and

inducing apoptosis and cell cycle arrest through

the Erk1/2 and Akt pathways. J Exp Clin Cancer

Res. 2019;38(1):93.

Refbacks

  • There are currently no refbacks.