Generic placeholder image

Current Cancer Drug Targets

Author(s): You Wu, Fenglin Zhang, Panling Xu and Ping Li*

DOI: 10.2174/0115680096274284231116104554

DownloadDownload PDF Flyer Cite As
Brucine Inhibits Proliferation of Pancreatic Ductal Adenocarcinoma through PI3K/AKT Pathway-induced Mitochondrial Apoptosis

Page: [749 - 759] Pages: 11

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Introduction: The purpose of this research was to settle the role of brucine in pancreatic ductal adenocarcinoma (PDAC) and the mechanisms involved.

Methods: The findings of this study suggest that brucine exerts inhibitory effects on cell growth, clonogenicity, and invasive potential of Panc02 and Mia Paca-2 cells. These effects may be linked to an increase in apoptotic-prone cell population.

Results: Gene sequencing data suggests that these effects are mediated through the induction of apoptosis. Experimental evidence further supports the notion that brucine reduces mitochondrial membrane potential and upregulates Bax expression while downregulating Bcl-2 expression. These effects are believed to be a result of brucine-mediated suppression of PI3K/Akt activity, which serves as a regulatory factor of mTOR, Bax, and Bcl-2. Suppression of PI3K activity enhances the tumor-suppressing effects of brucine.

Conclusion: Overall, these findings suggest that brucine has therapeutic potential as a remedy option for PDAC.

Keywords: Pancreatic ductal adenocarcinoma, brucine, apoptosis, PI3K/ AKT, mitochondria membrane potential, apoptotic- prone cell population.

Graphical Abstract

[1]
Dhillon, J.; Betancourt, M. Pancreatic ductal adenocarcinoma. Monogr. Clin. Cytol., 2020, 26, 74-91.
[http://dx.doi.org/10.1159/000455736] [PMID: 32987385]
[2]
Wang, L.; Wu, X.; Ruan, Y.; Zhang, X.; Zhou, X. Exosome-transmitted hsa_circ_0012634 suppresses pancreatic ductal adenocarcinoma progression through regulating miR-147b/HIPK2 axis. Cancer Biol. Ther., 2023, 24(1), 2218514.
[http://dx.doi.org/10.1080/15384047.2023.2218514] [PMID: 37326330]
[3]
Hung, H.C.; Fan, M.H.; Wang, D.; Miao, C.H.; Su, P.; Liu, C.L. Effect of chimeric antigen receptor T cells against protease-activated receptor 1 for treating pancreatic cancer. BMC Med., 2023, 21(1), 338.
[http://dx.doi.org/10.1186/s12916-023-03053-9] [PMID: 37667257]
[4]
Guilbaud, T.; Girard, E.; Lemoine, C.; Schlienger, G.; Alao, O.; Risse, O.; Berdah, S.; Chirica, M.; Moutardier, V.; Birnbaum, D.J. Intra-pancreatic distal cholangiocarcinoma and pancreatic ductal adenocarcinoma: A common short and long-term prognosis? Updates Surg., 2021, 73(2), 439-450.
[http://dx.doi.org/10.1007/s13304-021-00981-0] [PMID: 33486711]
[5]
Grossberg, A.J.; Chu, L.C.; Deig, C.R.; Fishman, E.K.; Hwang, W.L.; Maitra, A.; Marks, D.L.; Mehta, A.; Nabavizadeh, N.; Simeone, D.M.; Weekes, C.D.; Thomas, C.R., Jr Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J. Clin., 2020, 70(5), 375-403.
[http://dx.doi.org/10.3322/caac.21626] [PMID: 32683683]
[6]
Murimwa, G.Z.; Karalis, J.D.; Meier, J.; Nehrubabu, M.; Thornton, M.; Porembka, M.; Wang, S.; Zeh, H.J.; Yopp, A.C.; Polanco, P.M. Factors associated with failure to operate and its impact on survival in early-stage pancreatic cancer. J. Surg. Oncol., 2023, 128(4), 540-548.
[http://dx.doi.org/10.1002/jso.27357] [PMID: 37243895]
[7]
Liu, W.; Tang, X.; Fan, C.; He, G.; Wang, X.; Liang, X.; Bao, X. Chemical constituents, pharmacological action, antitumor application, and toxicity of Strychnine Semen from Strychnons pierriana A.W.Hill.: A review. J. Ethnopharmacol., 2023, 317, 116748.
[http://dx.doi.org/10.1016/j.jep.2023.116748] [PMID: 37348797]
[8]
Gao, Y.; Xin, D.; Liang, X.D.; Tang, Y. Effect of a combination of Atractylodes macrocephala extract with strychnine on the TLR4/NF-B/NLRP3 pathway in MH7A cells. Exp. Ther. Med., 2023, 25(2), 91.
[http://dx.doi.org/10.3892/etm.2023.11791] [PMID: 36761010]
[9]
Lei, Y.; Hou, F.; Wu, X.; Yi, Y.; Xu, F.; Gong, Q.; Gao, J. Brucine-induced neurotoxicity by targeting caspase 3: Involvement of PPARγ/NF-κB/apoptosis signaling pathway. Neurotox. Res., 2022, 40(6), 2117-2131.
[http://dx.doi.org/10.1007/s12640-022-00581-9] [PMID: 36151391]
[10]
Yan, W.; Zeng, Z.; Qin, F.; Xu, J.; Liao, Z.; Ouyang, M. Effects of brucine on mitochondrial apoptosis and expression of HSP70 in prostate cancer cells. Transl. Cancer Res., 2022, 11(3), 500-507.
[http://dx.doi.org/10.21037/tcr-22-209] [PMID: 35402184]
[11]
Lei, Y.; Hou, F.; Wu, X.; Yi, Y.; Xu, F.; Gong, Q.; Gao, J. Correction to: Brucine-induced neurotoxicity by targeting caspase 3: Involvement of PPARγ/NF-κB/apoptosis signaling pathway. Neurotox. Res., 2022, 40(6), 2132-2133.
[http://dx.doi.org/10.1007/s12640-022-00602-7] [PMID: 36342587]
[12]
Noman, M.; Qazi, N.G.; Rehman, N.U.; Khan, A. Pharmacological investigation of brucine anti-ulcer potential. Front. Pharmacol., 2022, 13, 886433.
[http://dx.doi.org/10.3389/fphar.2022.886433] [PMID: 36059979]
[13]
Razzaq, A; Hussain, G; Rasul, A; Xu, J; Zhang, Q; Malik, SA; Anwar, H; Aziz, N; Braidy, N; de Aguilar, JG Strychnos nux-vomica L. seed preparation promotes functional recovery and attenuates oxidative stress in a mouse model of sciatic nerve crush injury. BMC Complement. Med. Ther., 2020, 20(1), 181.
[14]
Li, S; Cui, Y; Li, M; Zhang, W; Sun, X; Xin, Z; Li, J Acteoside derived from cistanche improves glucocorticoid-induced osteoporosis by activating PI3K/AKT/mTOR pathway. J Invest Surg, 2023, 36(1), 2154578.
[15]
Zhao, Y.; Tang, J.; Yang, D.; Tang, C.; Chen, J. Staphylococcal enterotoxin M induced inflammation and impairment of bovine mammary epithelial cells. J. Dairy Sci., 2020, 103(9), 8350-8359.
[http://dx.doi.org/10.3168/jds.2019-17444] [PMID: 32622596]
[16]
Mortoglou, M.; Miralles, F.; Arisan, E.D.; Dart, A.; Jurcevic, S.; Lange, S.; Uysal-Onganer, P. microRNA-21 regulates stemness in pancreatic ductal adenocarcinoma cells. Int. J. Mol. Sci., 2022, 23(3), 1275.
[http://dx.doi.org/10.3390/ijms23031275] [PMID: 35163198]
[17]
Oria, V.O.; Bronsert, P.; Thomsen, A.R.; Föll, M.C.; Zamboglou, C.; Hannibal, L.; Behringer, S.; Biniossek, M.L.; Schreiber, C.; Grosu, A.L.; Bolm, L.; Rades, D.; Keck, T.; Werner, M.; Wellner, U.F.; Schilling, O. Proteome profiling of primary pancreatic ductal adenocarcinomas undergoing additive chemoradiation link ALDH1A1 to early local recurrence and chemoradiation resistance. Transl. Oncol., 2018, 11(6), 1307-1322.
[http://dx.doi.org/10.1016/j.tranon.2018.08.001] [PMID: 30172883]
[18]
Takhsha, F.S.; Vangestel, C.; Tanc, M.; De Bruycker, S.; Berg, M.; Pintelon, I.; Stroobants, S.; De Meyer, G.R.Y.; Van Der Veken, P.; Martinet, W. ATG4B inhibitor UAMC-2526 potentiates the chemotherapeutic effect of gemcitabine in a Panc02 mouse model of pancreatic ductal adenocarcinoma. Front. Oncol., 2021, 11, 750259.
[http://dx.doi.org/10.3389/fonc.2021.750259] [PMID: 34868951]
[19]
Soltek, S.; Karakhanova, S.; Golovastova, M.; D’Haese, J.G.; Serba, S.; Nachtigall, I.; Philippov, P.P.; Werner, J.; Bazhin, A.V. Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma. Naunyn Schmiedebergs Arch. Pharmacol., 2015, 388(11), 1121-1128.
[http://dx.doi.org/10.1007/s00210-015-1147-9] [PMID: 26105003]
[20]
Xu, H.; Chen, G.; Niu, Q.; Song, K.; Feng, Z.; Han, Z. Spindle and kinetochore-associated complex 3 promotes cell growth via the PI3K/AKT/GSK3β and PI3K/AKT/FOXO1 pathways and is a potential prognostic biomarker for oral squamous cell carcinoma. Oral Surg. Oral Med. Oral Pathol. Oral Radiol., 2022, 134(5), 599-614.
[http://dx.doi.org/10.1016/j.oooo.2022.06.010] [PMID: 36123287]
[21]
Li, C.; Fu, Y.; He, Y.; Huang, N.; Yue, J.; Miao, Y.; Lv, J.; Xiao, Y.; Deng, R.; Zhang, C.; Huang, M. Knockdown of LINC00511 enhances radiosensitivity of lung adenocarcinoma via regulating miR-497-5p/SMAD3. Cancer Biol. Ther., 2023, 24(1), 2165896.
[http://dx.doi.org/10.1080/15384047.2023.2165896] [PMID: 36861928]
[22]
Bozza, A.; Bernardi, M.; Catanzaro, D.; Chieregato, K.; Merlo, A.; Astori, G. Enalaprilat and losartan decrease erythroid precursors frequency in cells from patients with polycythemia vera. Hematology, 2023, 28(1), 2182056.
[http://dx.doi.org/10.1080/16078454.2023.2182056] [PMID: 36856520]
[23]
Yang, C.H.; Wu, Y.T.; Tung, K.L.; Huang, B.M.; Lan, Y.Y. Qing Yan Li Ge Tang Induces Apoptosis in Human OEC-M1 Oral Cancer Cells. Altern. Ther. Health Med., 2023, AT9071.
[PMID: 37678860]
[24]
Yang, T.; Yu, R.; Cheng, C.; Huo, J.; Gong, Z.; Cao, H.; Hu, Y.; Dai, B.; Zhang, Y. Cantharidin induces apoptosis of human triple negative breast cancer cells through mir-607-mediated downregulation of EGFR. J. Transl. Med., 2023, 21(1), 597.
[http://dx.doi.org/10.1186/s12967-023-04483-y] [PMID: 37670360]
[25]
Lv, X.; Lin, Y.; Zhu, X.; Cai, X. Isoalantolactone suppresses gallbladder cancer progression via inhibiting the ERK signalling pathway. Pharm. Biol., 2023, 61(1), 556-567.
[http://dx.doi.org/10.1080/13880209.2023.2191645] [PMID: 36994917]
[26]
Zhao, M.; Fu, L.; Xu, P.; Wang, T.; Li, P. Network pharmacology and experimental validation to explore the effect and mechanism of kanglaite injection against triple-negative breast cancer. Drug Des. Devel. Ther., 2023, 17, 901-917.
[http://dx.doi.org/10.2147/DDDT.S397969] [PMID: 36998242]
[27]
Wu, M; Sun, X; Wang, T; Zhang, M; Li, P RPS1 knockdown inhibits angiogenic vascular mimicry in human triple negative breast cancer cells. Clin Transl Oncol, 2022, 24(1), 145-153.
[http://dx.doi.org/10.1007/s12094-021-02676-9]
[28]
Wang, J.; Wang, Z.; Jia, W.; Gong, W.; Dong, B.; Wang, Z.; Zhou, M.; Tian, C. The role of costimulatory molecules in glioma biology and immune microenvironment. Front. Genet., 2022, 13, 1024922.
[http://dx.doi.org/10.3389/fgene.2022.1024922] [PMID: 36437961]
[29]
Zhou, S.; Han, Y.; Yang, R.; Pi, X.; Li, J. TIMM13 as a prognostic biomarker and associated with immune infiltration in skin cutaneous melanoma (SKCM). Front. Surg., 2022, 9, 990749.
[http://dx.doi.org/10.3389/fsurg.2022.990749] [PMID: 36061054]
[30]
You, J.; Wu, Q.; Li, Y.; Li, X.; Lin, Z.; Huang, J.; Xue, Y.; Gulimiran, A.; Pan, Y. Lentinan induces apoptosis of mouse hepatocellular carcinoma cells through the EGR1/PTEN/AKT signaling axis. Oncol. Rep., 2023, 50(1), 142.
[http://dx.doi.org/10.3892/or.2023.8579] [PMID: 37264970]
[31]
Peng, Z.; Yang, X.; Zhang, H.; Yin, M.; Luo, Y.; Xie, C. MiR-29b-3p aggravates NG108-15 cell apoptosis triggered by fluorine combined with aluminum. Ecotoxicol. Environ. Saf., 2021, 224, 112658.
[http://dx.doi.org/10.1016/j.ecoenv.2021.112658] [PMID: 34425535]
[32]
Xie, J.; Cheng, C.; Zhu, X.Y.; Shen, Y.H.; Song, L.B.; Chen, H.; Chen, Z.; Liu, L.M.; Meng, Z.Q. Magnesium transporter protein solute carrier family 41 member 1 suppresses human pancreatic ductal adenocarcinoma through magnesium-dependent Akt/mTOR inhibition and Bax-associated mitochondrial apoptosis. Aging, 2019, 11(9), 2681-2698.
[http://dx.doi.org/10.18632/aging.101940] [PMID: 31076559]
[33]
Ren, S; Wang, Y; Zhang, Y; Yan, P; Xiao, D; Zhao, Y; Jia, W; Ding, L; Dong, H; Wei, C Inhibition of colon carcinogenesis by a standardized cannabis sativa extract with high content of cannabidiol. Biomed Pharmacother, 2023, 21(5), 631-639.
[http://dx.doi.org/10.1016/j.biopha.2023.115253]
[34]
Jiao, Y.; Zhang, X.; Yang, H.; Ma, H.; Zou, J. Mesoporous tantalum oxide nanomaterials induced cardiovascular endothelial cell apoptosis via mitochondrial-endoplasmic reticulum stress apoptotic pathway. Drug Deliv., 2023, 30(1), 108-120.
[http://dx.doi.org/10.1080/10717544.2022.2147251] [PMID: 36533874]
[35]
Roca-Agujetas, V.; de Dios, C.; Lestón, L.; Marí, M.; Morales, A.; Colell, A. Recent insights into the mitochondrial role in autophagy and its regulation by oxidative stress. Oxid. Med. Cell. Longev., 2019, 2019, 1-16.
[http://dx.doi.org/10.1155/2019/3809308] [PMID: 31781334]
[36]
Zhao, R.; Zhao, Q.; Wang, X.; Chen, X.; Liang, C.; Xiao, Q.; Yang, S.; Tan, S. Yi-Qi-Jian-Pi formula inhibits hepatocyte pyroptosis through the IDH2-driven tricarboxylic acid cycle to reduce liver injury in acute-on-chronic liver failure. J. Ethnopharmacol., 2023, 317, 116683.
[http://dx.doi.org/10.1016/j.jep.2023.116683] [PMID: 37315653]
[37]
Wang, F; Ma, Q; Dong, X; Wang, T; Ma, C circ-Gucy1a2 protects mice from cerebral ischemia-reperfusion injury by attenuating neuronal apoptosis and mitochondrial membrane potential loss. J Invest Surg, 2023, 36(1), 2152509.
[38]
Liu, L.; Yu, Z.; Chen, J.; Liu, B.; Wu, C.; Li, Y.; Xu, J.; Li, P. Lucialdehyde B suppresses proliferation and induces mitochondria-dependent apoptosis in nasopharyngeal carcinoma CNE2 cells. Pharm. Biol., 2023, 61(1), 918-926.
[http://dx.doi.org/10.1080/13880209.2023.2220754] [PMID: 37323017]
[39]
Li, Y.; Hou, H.; Liu, Z.; Tang, W.; Wang, J.; Lu, L.; Fu, J.; Gao, D.; Zhao, F.; Gao, X.; Ling, P.; Wang, F.; Sun, F.; Tan, H. CD44 targeting nanodrug based on chondroitin sulfate for melanoma therapy by inducing mitochondrial apoptosis pathways. Carbohydr. Polym., 2023, 320, 121255.
[http://dx.doi.org/10.1016/j.carbpol.2023.121255] [PMID: 37659829]
[40]
Li, J.; Sun, X.; Wang, X.; Yang, N.; Xie, H.; Guo, H.; Lu, L.; Xie, X.; Zhou, L.; Liu, J.; Zhang, W.; Lu, L. PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release. Acta Pharmacol. Sin., 2023.
[http://dx.doi.org/10.1038/s41401-023-01151-1] [PMID: 37684381]
[41]
Zhou, S.; Gao, X.; Chen, C.; Zhang, J.; Zhang, Y.; Zhang, L.; Yan, X. Porcine cardiac blood - Salvia miltiorrhiza root alleviates cerebral ischemia reperfusion injury by inhibiting oxidative stress induced apoptosis through PI3K/AKT/Bcl-2/Bax signaling pathway. J. Ethnopharmacol., 2023, 316, 116698.
[http://dx.doi.org/10.1016/j.jep.2023.116698] [PMID: 37286116]
[42]
Safari, F.; Dadvar, F. In vitro evaluation of autophagy and cell death induction in Panc1 pancreatic cancer by secretome of hAMSCs through downregulation of p-AKT/p-mTOR and upregulation of p-AMPK/ULK1 signal transduction pathways. Tissue Cell, 2023, 84, 102160.
[http://dx.doi.org/10.1016/j.tice.2023.102160] [PMID: 37482027]
[43]
Ju, W.K.; Shim, M.S.; Kim, K.Y.; Park, T.L.; Ahn, S.; Edwards, G.; Weinreb, R.N. Inhibition of cAMP/PKA pathway protects optic nerve head astrocytes against oxidative stress by Akt/Bax phosphorylation-mediated Mfn1/2 oligomerization. Oxid. Med. Cell. Longev., 2019, 2019, 1-16.
[http://dx.doi.org/10.1155/2019/8060962] [PMID: 31781352]
[44]
Wang, F; Yin, Y; Nie, X; Zou, Y; Tong, X; Tong, Y; Zhou, J; Tan, Y Protocatechuic acid alleviates polycystic ovary syndrome symptoms in mice by PI3K signaling in granulosa cells to relieve ROS pressure and apoptosis. Gynecol Endocrinol., 2023, 39(1), 2228917.
[http://dx.doi.org/10.1080/09513590.2023.2228917]
[45]
Azhati, B.; Reheman, A.; Dilixiati, D.; Rexiati, M. FTO-stabilized miR-139–5p targets ZNF217 to suppress prostate cancer cell malignancies by inactivating the PI3K/Akt/mTOR signal pathway. Arch. Biochem. Biophys., 2023, 741, 109604.
[http://dx.doi.org/10.1016/j.abb.2023.109604] [PMID: 37080415]
[46]
Heinicke, U.; Kupka, J.; Fichter, I.; Fulda, S. Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma. Oncogene, 2016, 35(28), 3729-3741.
[http://dx.doi.org/10.1038/onc.2015.440] [PMID: 26616861]
[47]
Abdallah, M.H.; Lila, A.S.A.; Unissa, R.; Elsewedy, H.S.; Elghamry, H.A.; Soliman, M.S. Brucine-loaded ethosomal gel: Design, optimization, and anti-inflammatory activity. AAPS PharmSciTech, 2021, 22(8), 269.
[http://dx.doi.org/10.1208/s12249-021-02113-8] [PMID: 34762193]
[48]
Lu, S.; Wang, X.; He, C.; Wang, L.; Liang, S.; Wang, C.; Li, C.; Luo, T.; Feng, C.; Wang, Z.; Chi, G.; Ge, P. ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta Pharmacol. Sin., 2021, 42(10), 1690-1702.
[http://dx.doi.org/10.1038/s41401-021-00700-w] [PMID: 34112960]
[49]
Yogosawa, S.; Yoshida, K. Tumor suppressive role for kinases phosphorylating p53 in DNA damage-induced apoptosis. Cancer Sci., 2018, 109(11), 3376-3382.
[http://dx.doi.org/10.1111/cas.13792] [PMID: 30191640]
[50]
Sadri, F.; Hosseini, S.; Rezaei, Z.; Fereidouni, M. Hippo-YAP/TAZ signaling in breast cancer: Reciprocal regulation of microRNAs and implications in precision medicine. Genes Dis., 2024, 11(2), 760-771.
[http://dx.doi.org/10.1016/j.gendis.2023.01.017] [PMID: 37692482]
[51]
Jia, Q.; Liao, X.; Xu, B.; Li, Y.; Liang, L. MiR-128-1-5p inhibits cell proliferation and induces cell apoptosis via targeting PRKCQ in colorectal cancer. Cancer Biol. Ther., 2023, 24(1), 2226421.
[http://dx.doi.org/10.1080/15384047.2023.2226421] [PMID: 37358216]
[52]
Wang, H.; Ren, R.; Yang, Z.; Cai, J.; Du, S.; Shen, X. The COL11A1/Akt/CREB signaling axis enables mitochondrial-mediated apoptotic evasion to promote chemoresistance in pancreatic cancer cells through modulating BAX/Bcl-2 function. J. Cancer, 2021, 12(5), 1406-1420.
[http://dx.doi.org/10.7150/jca.47032] [PMID: 33531986]
[53]
Chaudhary, M.R.; Chaudhary, S.; Sharma, Y.; Singh, T.A.; Mishra, A.K.; Sharma, S.; Mehdi, M.M. Aging, oxidative stress and degenerative diseases: Mechanisms, complications and emerging therapeutic strategies. Biogerontology, 2023, 24(5), 609-662.
[http://dx.doi.org/10.1007/s10522-023-10050-1] [PMID: 37516673]
[54]
Bhatti, J.S.; Kaur, S.; Mishra, J.; Dibbanti, H.; Singh, A.; Reddy, A.P.; Bhatti, G.K.; Reddy, P.H. Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis., 2023, 1869(7), 166798.
[http://dx.doi.org/10.1016/j.bbadis.2023.166798] [PMID: 37392948]
[55]
Brunelle, J.K.; Letai, A. Control of mitochondrial apoptosis by the Bcl-2 family. J. Cell Sci., 2009, 122(4), 437-441.
[http://dx.doi.org/10.1242/jcs.031682] [PMID: 19193868]
[56]
Yamaguchi, R.; Lartigue, L.; Perkins, G. Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy. Pharmacol. Ther., 2019, 195, 13-20.
[http://dx.doi.org/10.1016/j.pharmthera.2018.10.009] [PMID: 30347215]
[57]
Wang, J.; Yang, D.; Luo, Q.; Qiu, M.; Zhang, L.; Li, B.; Chen, H.; Yi, H.; Yan, X.; Li, S.; Sun, J. APG-1252-12A induces mitochondria-dependent apoptosis through inhibiting the antiapoptotic proteins Bcl-2/Bcl-xl in HL-60 cells. Int. J. Oncol., 2017, 51(2), 563-572.
[http://dx.doi.org/10.3892/ijo.2017.4028] [PMID: 28586007]
[58]
Bai, C.; Zhao, J.; Su, J.; Chen, J.; Cui, X.; Sun, M.; Zhang, X. Curcumin induces mitochondrial apoptosis in human hepatoma cells through BCLAF1-mediated modulation of PI3K/AKT/GSK-3β signaling. Life Sci., 2022, 306, 120804.
[http://dx.doi.org/10.1016/j.lfs.2022.120804] [PMID: 35882275]
[59]
Zhang, B.F.; Xing, L.; Cui, P.F.; Wang, F.Z.; Xie, R.L.; Zhang, J.L.; Zhang, M.; He, Y.J.; Lyu, J.Y.; Qiao, J.B.; Chen, B.A.; Jiang, H.L. Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine. Biomaterials, 2015, 61, 178-189.
[http://dx.doi.org/10.1016/j.biomaterials.2015.05.027] [PMID: 26004233]
[60]
Jiaying, Y.; Bo, S.; Xiaolu, W.; Yanyan, Z.; Hongjie, W.; Nan, S.; Bo, G.; Linna, W.; Yan, Z.; Wenya, G.; Keke, L.; Shan, J.; Chuan, L.; Yu, Z.; Qinghe, Z.; Haiyu, Z. Arenobufagin-loaded PEG-PLA nanoparticles for reducing toxicity and enhancing cancer therapy. Drug Deliv., 2023, 30(1), 2177362.
[http://dx.doi.org/10.1080/10717544.2023.2177362] [PMID: 36772846]
[61]
Wang, Z.; Chen, K.; Zhang, K.; He, K.; Zhang, D.; Guo, X.; Huang, T.; Hu, J.; Zhou, X.; Nie, S. Agrocybe cylindracea fucoglucogalactan induced lysosome-mediated apoptosis of colorectal cancer cell through H3K27ac-regulated cathepsin D. Carbohydr. Polym., 2023, 319, 121208.
[http://dx.doi.org/10.1016/j.carbpol.2023.121208] [PMID: 37567726]
[62]
Roche, M.E.; Ko, Y.H.; Domingo-Vidal, M.; Lin, Z.; Whitaker-Menezes, D.; Birbe, R.C.; Tuluc, M.; Győrffy, B.; Caro, J.; Philp, N.J.; Bartrons, R.; Martinez-Outschoorn, U. TP53 induced glycolysis and apoptosis regulator and monocarboxylate transporter 4 drive metabolic reprogramming with c-MYC and NFkB activation in breast cancer. Int. J. Cancer, 2023, 153(9), 1671-1683.
[http://dx.doi.org/10.1002/ijc.34660] [PMID: 37497753]
[63]
Seshadri, V.D. Brucine promotes apoptosis in cervical cancer cells (ME-180) via suppression of inflammation and cell proliferation by regulating PI3K / AKT / MTOR signaling pathway. Environ. Toxicol., 2021, 36(9), 1841-1847.
[http://dx.doi.org/10.1002/tox.23304] [PMID: 34076332]
[64]
Deng, X.; Yin, F.; Lu, X.; Cai, B.; Yin, W. The apoptotic effect of brucine from the seed of Strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+ involved mitochondrial pathway. Toxicol. Sci., 2006, 91(1), 59-69.
[http://dx.doi.org/10.1093/toxsci/kfj114] [PMID: 16443926]
[65]
Xue, KH; Jiang, YF; Bai, JY; Zhang, DZ; Chen, YH; Ma, JB; Zhu, ZJ; Wang, X; Guo, P Melatonin suppresses Akt/mTOR/S6K activity, induces cell apoptosis, and synergistically inhibits cell growth with sunitinib in renal carcinoma cells via reversing Warburg effect. Redox Rep, 2023, 28(1), 2251234.
[66]
Jiang, X.; Lin, Y.; Zhao, M.; Li, Y.; Ye, P.; Pei, R.; Lu, Y.; Jiang, L. Platycodin D induces apoptotic cell death through PI3K/AKT and MAPK/ERK pathways and synergizes with venetoclax in acute myeloid leukemia. Eur. J. Pharmacol., 2023, 956, 175957.
[http://dx.doi.org/10.1016/j.ejphar.2023.175957] [PMID: 37541375]
[67]
Liu, X.; Fan, L.; Li, J.; Bai, Z.; Wang, Y.; Liu, Y.; Jiang, H.; Tao, A.; Li, X.; Zhang, H.; Tan, N. Mailuoning oral liquid attenuates convalescent cerebral ischemia by inhibiting AMPK/mTOR-associated apoptosis and promoting CREB/BDNF-mediated neuroprotection. J. Ethnopharmacol., 2023, 317, 116731.
[http://dx.doi.org/10.1016/j.jep.2023.116731] [PMID: 37277084]
[68]
Xiao, P.; Chen, X.; Dong, Z.; Fan, W.; Chen, Y.; Su, J.; Wang, Q.; Ma, L. BNIP3 overexpression may promote myeloma cell apoptosis by enhancing sensitivity to bortezomib via the p38 MAPK pathway. Hematology, 2023, 28(1), 2231739.
[http://dx.doi.org/10.1080/16078454.2023.2231739] [PMID: 37401850]
[69]
Zhai, B.W.; Zhao, H.; Zhu, H.L.; Huang, H.; Zhang, M.Y.; Fu, Y.J. Triterpene acids from Rosa roxburghii Tratt fruits exert anti-hepatocellular carcinoma activity via ROS/JNK signaling pathway-mediated cell cycle arrest and mitochondrial apoptosis. Phytomedicine, 2023, 119, 154960.
[http://dx.doi.org/10.1016/j.phymed.2023.154960] [PMID: 37531905]
[70]
Du, D.; Wang, S.; Li, T.; Liu, Z.; Yang, M.; Sun, L.; Yuan, S. RHNO1 disruption inhibits cell proliferation and induces mitochondrial apoptosis via PI3K/Akt pathway in hepatocellular carcinoma. Biochem. Biophys. Res. Commun., 2023, 673, 96-105.
[http://dx.doi.org/10.1016/j.bbrc.2023.05.119] [PMID: 37364391]
[71]
Jan, R.; Chaudhry, G.S. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv. Pharm. Bull., 2019, 9(2), 205-218.
[http://dx.doi.org/10.15171/apb.2019.024] [PMID: 31380246]
[72]
Liu, C.; Wang, Q.; Niu, L. Sufentanil inhibits Pin1 to attenuate renal tubular epithelial cell ischemia–reperfusion injury by activating the PI3K/AKT/FOXO1 pathway. Int. Urol. Nephrol., 2023, 55(8), 1903-1916.
[http://dx.doi.org/10.1007/s11255-023-03651-9] [PMID: 37300758]
[73]
Chen, T.; Bao, S.; Chen, J.; Zhang, J.; Wei, H.; Hu, X.; Liang, Y.; Li, J.; Yan, S. Xiaojianzhong decoction attenuates aspirin-induced gastric mucosal injury via the PI3K/AKT/mTOR/ULK1 and AMPK/ULK1 pathways. Pharm. Biol., 2023, 61(1), 1234-1248.
[http://dx.doi.org/10.1080/13880209.2023.2243998] [PMID: 37602379]
[74]
Huang, X.; You, L.; Nepovimova, E.; Psotka, M.; Malinak, D.; Valko, M.; Sivak, L.; Korabecny, J.; Heger, Z.; Adam, V.; Wu, Q.; Kuca, K. Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK). J. Enzyme Inhib. Med. Chem., 2023, 38(1), 2237209.
[http://dx.doi.org/10.1080/14756366.2023.2237209] [PMID: 37489050]
[75]
Liu, G; Zhang, S; Yang, S; Shen, C; Shi, C; Diao, W CircDiaph3 influences PASMC apoptosis by regulating PI3K/AKT/mTOR pathway through IGF1R. 3 Biotech, 2023, 13(10), 342.
[76]
Wang, Z.; Jiang, X.; Zhang, L.; Chen, H. Protective effects of Althaea officinalis L. extract against N -diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats through antioxidative, anti-inflammatory, mitochondrial apoptosis and PI3K /Akt/ MTOR signaling pathways. Food Sci. Nutr., 2023, 11(8), 4756-4772.
[http://dx.doi.org/10.1002/fsn3.3455] [PMID: 37576045]
[77]
Zhou, Y.; Yuan, F.; Jia, C.; Chen, F.; Li, F.; Wang, L. MiR-497-3p induces Premature ovarian failure by targeting KLF4 to inactivate Klotho/PI3K/AKT/mTOR signaling pathway. Cytokine, 2023, 170, 156294.
[http://dx.doi.org/10.1016/j.cyto.2023.156294] [PMID: 37549487]
[78]
Üremiş, M.M.; Üremiş, N.; Türköz, Y. Cucurbitacin E shows synergistic effect with sorafenib by inducing apoptosis in hepatocellular carcinoma cells and regulates Jak/Stat3, ERK/MAPK, PI3K/Akt/mTOR signaling pathways. Steroids, 2023, 198, 109261.
[http://dx.doi.org/10.1016/j.steroids.2023.109261] [PMID: 37355001]
[79]
Zhao, Z; Yang, Q; Zhou, T; Liu, C; Sun, M; Cui, X; Zhang, X Anticancer potential of Bacillus coagulans MZY531 on mouse H22 hepatocellular carcinoma cells via anti-proliferation and apoptosis induction. BMC Complement. Med. Ther., 2023, 23(1), 318.
[http://dx.doi.org/10.1186/s12906-023-04120-7]