PTEN-Akt/mTOR Expression Level in A549 Lung Cancer Cells in Response to Cisplatin, Carotenoids, and their Combination: http://www.doi.org/10.26538/tjnpr/v8i1.9

Agustina D.R. Nurcahyanti; Teresa F. Tenia; Ferdy Candra

Authors

Agustina D.R. Nurcahyanti Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
Teresa F. Tenia Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
Ferdy Candra Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia

Keywords:

p53, Akt/mTOR, PTEN, carotenoids, cisplatin, lung cancer

Abstract

The negative impacts of cisplatin often lead to undesirable side effects. Moreover, the issue of resistance has been recognized as a substantial hurdle in achieving effective therapeutic results. Multiple studies have emphasized the reliance of particular tumors, such as lung cancer, on the PI3K/Akt/mTOR pathway. Cisplatin is known to initiate Akt regulation in cancer cells, which ultimately makes these cells resistant to apoptosis. Despite the existence of specific inhibitors tailored to intervene in the PI3K/Akt/mTOR pathway, the continuously evolving epigenetic environment of this cascade plays a role in the development of resistance in cancer cells against these inhibitors. Antioxidants, exemplified by carotenoids, have garnered attention due to their versatile roles. They function as pro-oxidants, initiating apoptosis in cancer cells, while also acting as antioxidants that promote the restoration of normal cell function. This study aimed to examine the influence of bixin and fucoxanthin, both separately and in conjunction with cisplatin, on the transcriptional levels of PTEN, Akt/mTOR, and the tumor suppressor p53 in A549 cell lines. Cell viability was assessed using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Drug combinations were performed in accordance with the Chou-Talalay theorem. The Real-Time Quantitative-Polymerase Chain Reaction (RT-q-PCR) method was employed to evaluate the expression levels of the PI3K/Akt/mTOR genes. The ongoing study furnished proof that carotenoids, particularly bixin and fucoxanthin, showcase anticancer attributes and have the potential to complement cisplatin chemotherapy in lung cancer cells. This potential is realized by influencing the modulation of PTEN and the decrease in Akt and mTOR expression.

References

Kanavos P. The rising burden of cancer in the developing world. Ann. Oncol. 2006; 17:15–23.

Cancer is on the rise in developing countries | News | Harvard T.H. Chan School of Public Health [Internet]. [cited 2022 Nov 9]. Available from: https://www.hsph.harvard.edu/news/magazine/shadow-epidemic/

Cancer rates by Human Development Index | WCRF International [Internet]. [cited 2022 Nov 9]. Available from: https://www.wcrf.org/cancer-trends/cancer-rates-human-development-index/

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

Nagasaka M, Abdallah N, Crosby M, Thummala N, Patel D, Wozniak AJ, Gadgeel S, Abrams J, Sukuri A. A retrospective study evaluating the pretreatment tumor volume (PTV) in non-small cell lung cancer (NSCLC) as a predictor of response to program death-1 (PD-1) inhibitors. Lung Cancer: Targets and Therapy. 2019;10:95.

Harada G, Neffa MFBV, Bonadio RC, Mendoza EZ, Caparica R, Lauricella LL, Takagaki TY, Roitberg FSR, Terra RM, Castro GD. Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer. J Bras Pneumol. 2021;47(3)e20200378.

Gonzalez VM, Fuertes MA, Alonso C, Perez JM. Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol. 2001;59(4):657–63.

Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M, Kroemer G. Systems biology of cisplatin resistance: past, present and future. Cell Death Dis. 2014;5(5):e1257–e1257.

Nurcahyanti ADR, Kusmita L, Wink M. Bixin and fucoxanthin sensitize human lung cancer and cervical cancer cell to cisplatin in vitro. BMC Res Notes. 2021;14(1):1–8.

Nurcahyanti ADR, Jap A, Lady J, Prismawan D, Sharopov F, Daoud R, Wink M, Sobeh M. Function of selected natural antidiabetic compounds with potential against cancer via modulation of the PI3K/AKT/mTOR cascade. Biomed Pharmacother. 2021;144.

Zhang J, Zhang LL, Shen L, Xu XM, Yu HG. Regulation of AKT gene expression by cisplatin. Oncol Lett. 2013;5(3):756-760.

Sanaei MJ, Razi S, Pourbagheri-Sigaroodi A, Bashash D. The PI3K/Akt/mTOR pathway in lung cancer; oncogenic alterations, therapeutic opportunities, challenges, and a glance at the application of nanoparticles. Transl Oncol. 2022;18:101364.

Papa A, Pandolfi PP. The PTEN–PI3K axis in cancer. Biomolecules. 2019;9(4):153-164.

Issinger OG, Guerra B. Phytochemicals in cancer and their effect on the PI3K/AKT-mediated cellular signalling. Biomed Pharmacother. 2021;139:111650.

Shin J, Song MH, Oh JW, Keum YS, Saini RK. Pro-oxidant actions of carotenoids in triggering apoptosis of cancer cells: A review of emerging evidence. Antioxidants. 2020;9(6):1–17.

Ming JX, Wang ZC, Huang Y, Ohishi H, Wu RJ, Shao Y, Wang H, Qin MY, Wu ZL, Li YY, Zhou SC, Chen H, Liu H, Xu R. Fucoxanthin extracted from Laminaria Japonica inhibits metastasis and enhances the sensitivity of lung cancer to Gefitinib. J Ethnopharmacol. 2021;265:113302.

Nurcahyanti AD, Kusmita L, Wink M. Bixin and fucoxanthin sensitize human lung cancer and cervical cancer cell to cisplatin in vitro. BMC Res Notes. 2021;14(1):1–8.

Nurcahyanti AD, Wink M. L-Canavanine potentiates the cytotoxicity of doxorubicin and cisplatin in arginine deprived human cancer cells. PeerJ. 2016;4(1):265:113302.

Nurcahyanti AD, Wink M. Cytotoxic potentiation of vinblastine and paclitaxel by L-canavanine in human cervical cancer and hepatocellular carcinoma cells. Phytomedicine. 2015;22(14):1232–7.

TP53 gene: MedlinePlus Genetics [Internet]. [cited 2022 Nov 10]. Available from: https://medlineplus.gov/genetics/gene/tp53/

Lakin ND, Jackson SP. Regulation of p53 in response to DNA damage. Oncogene. 1999;18(53):7644–55.

Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364.

Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997;275(5303):1129–32.

Garg S, Afzal S, Elwakeel A, Sharma D, Radhakrishnan N, Dhanjal JK, Sundar D, Kaul SC, Wadha R. Marine 24.carotenoid fucoxanthin possesses anti-metastasis activity: Molecular Evidence. Mar Drugs. 2019;17(6).

Putri JF, Bhargava P, Dhanjal JK, Yaguchi T, Sundar D, Kaul SC, Wadhwa R. Mortaparib, a novel dual inhibitor of mortalin and PARP1, is a potential drug candidate for ovarian and cervical cancers. J Exp Clin Cancer Res. 2019;38(1):1–15.

Kim KN, Heo SJ, Kang SM, Ahn G, Jeon YJ. Fucoxanthin induces apoptosis in human leukemia HL-60 cells through a ROS-mediated Bcl-xL pathway. Toxicol In Vitro. 2010;24(6):1648–54.

Cordani M, Butera G, Pacchiana R, Masetto F, Mullappilly N, Riganti C, Donadelli M. Mutant p53-associated molecular mechanisms of ROS regulation in cancer cells. Biomolecules. 2020;10(3):361.

Nitulescu GM, Van De Venter M, Nitulescu G, Ungurianu A, Juzenas P, Peng Q, Olaru OT, Gradinaru D, Tsatsakis A, Tsoukalas D, Spandidos DA, Margina D. The Akt pathway in oncology therapy and beyond (Review). Int J Oncol. 2018;53(6):2319–31.

Fusco N, Sajjadi E, Venetis K, Gaudioso G, Lopez G, Corti C, Rocco EG, Criscitiello C, Malapelle U, Invernizzi M. PTEN alterations and their role in cancer management: Are we making headway on precision medicine? Genes. 2020;11(7):1–19.

Papa A, Pandolfi PP. The PTEN–PI3K axis in cancer. Biomolecules. 2019;9(4):153.

Chan S. Targeting the mammalian target of rapamycin (mTOR): A new approach to treating cancer. Br J Cancer. 2004;9:1420–4.

Tian T, Li X, Zhang J. mTOR Signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci. 2019;20(3).

Yin S, Liu L, Gan W. The roles of post-translational modifications on mTOR signaling. Int J Mol Sci. 2021;22(4):1–28.

Okoro BC, Dokunmu TM, Ugbogu EA, Iheagwam FN, Osaigbovo DI, Sokoyo IA, Iweala EEJ. BRAF inhibitors in carcinogenesis and their clinical implications: A review. Trop J Nat Prod Res. 2022;6(11):1746-1754.

Al-Salim YM, Al-Asadi RH. Synthesis, anti-breast cancer activity, and molecular docking studies of thiourea benzamide derivatives and their complexes with copper ion. Trop J Nat Prod Res. 2023;7(6):3158-3167.