Yalçın ERZURUMLU, Deniz ÇATAKLI, Hatice Kübra DOĞAN

Prostat Kanseri Hücrelerinde Kafein Sisplatinin Anti-tümorijenik Etkisini Güçlendirir

Giriş ve Amaç: Günümüzde prostat kanseri (PCa) tedavisinde cerrahi, androjen ablasyon tedavisi ve kemoterapi gibi çok sayıda yaklaşım bulunmaktadır. Ancak, androjen reseptörü (AR) hedefli terapiler veya mevcut terapilerin doğal bileşiklerle kombinasyonunun geliştirilmesine halen ihtiyaç duyulmaktadır. Sisplatin çeşitli solid tümörlerin tedavisinde yaygın olarak kullanılan ilk platin bazlı kemoterapötik ajanlardan birisidir. Kafein (Cfn) altmıştan fazla bitki türünde doğal olarak bulunan ve dünya çapında en sık tüketilen nöroaktif doğal ürün olan ksantin türevi bir alkaloittir. Anti-oksidan, anti-inflamatuar ve anti-kanser gibi çeşitli biyokimyasal etkilere sahiptir. Bu çalışmada, yaygın olarak kullanılan bir kemoterapötik ajan olan sisplatinin kafein ile kombinasyonunun PCa hücreleri üzerindeki etkilerini araştırdık. Gereç ve Yöntemler: Total-p38 MAPK, fosforile-(Thr180/Tyr182) p38 MAPK, total NF-κB, fosforile-(Ser536) NF-κB, Siklin A2, Siklin B1, Siklin E1, AR, PSA ve VEGF-A protein ifadesi düzeyleri immünoblotlama çalışmaları ile insan prostat kanseri hücre hattı olan LNCaP hücrelerinde incelenmiştir. Sonuçlar: Elde ettiğimiz sonuçlar, Cfn'nin siklin A2, B1 ve E1 düzeylerini azaltarak, androjenik sinyal ile ilişkili AR ve PSA düzeylerini ve anjiyojenik düzenleyici VEGF-A protein düzeylerini baskılayarak sisplatinin LNCaP hücreleri üzerindeki etkisini sinerjistik olarak doz-bağımlı bir şekilde arttırdığını gösterdi. Ayrıca, sisplatin kaynaklı p38 MAPK ve NF-κB aktivasyonunun Cfn uygulaması tarafından baskılandığını belirlendi. Tartışma: Sonuçlarımız, sisplatin ve Cfn'nin kombine kullanımının kemoterapötiklerin toksik dozunu azaltarak PCa tedavisinde etkili bir terapötik yaklaşım sunabileceğini göstermektedir.

Anahtar Kelimeler:

Androjen reseptörü, Kafein, Sisplatin, Prostat kanseri

Caffeine Potentiate the Anti-tumorigenic Effect of Cisplatin in Prostate Cancer Cells

Objective: Today, there are numerous approaches for prostate cancer (PCa) treatment, such as surgery, androgen ablation therapy and chemotherapy. However, there is still a need to develop new androgen receptor (AR)-targeted therapies or a combination of existing therapies with natural compounds. Cisplatin is the first platinum-based anti-cancer drug which is one of the widely used chemotherapeutic agents in the treatment of various solid tumors. Caffeine (Cfn) is a xanthine-derived alkaloid that occurs naturally in more than sixty plant species and is the most frequently consumed neuroactive natural product globally. It has various biochemical effects, including anti-oxidant, anti-inflammatory and anti-cancer. In the present study, we investigated the effects of the widely used chemotherapeutic agent cisplatin and its combination with caffeine on PCa cells. Materials and Methods: We examined the protein expression level of total-p38 mitogen-activated protein kinase (MAPK) phospho-(Thr180/Tyr182) p38 MAPK, total nuclear factor-κB (NF-κB), phospho-(Ser536) NF-κB, cyclin A2, cyclin B1, cyclin E1, androgen receptor (AR), prostate-specific antigen (PSA) and vascular endothelial growth factor A (VEGF-A) in human prostate cancer cell line LNCaP by immunoblotting assay. Results: Our results indicated that Cfn synergistically increased the effect of cisplatin on LNCaP cells in a dose-dependent manner by decreasing the cyclin A2, B1 and E1 levels, reducing androgenic signal-related AR and PSA levels and angiogenic regulator VEGF-A levels. Also, we found that cisplatin-induced p38 MAPK and NF-κB activation were suppressed by Cfn administration. Conclusion: Our results suggest that combinatory usage of cisplatin and the cost-effective agent Cfn may exhibit an effective therapeutic approach in the treatment of PCa by reducing the toxic dose of chemotherapeutics.

Keywords:

Androgen receptor, Caffeine, Cisplatin, Prostate cancer,

PDF

___

Siegel, RL, Miller, KD, Fuchs, HE, Jemal, A, Cancer statistics, 2021, CA Cancer J Clin., 2021, 71, 7–33.
Handa, S, Hans, B, Goel, S, Bashorun, HO, Dovey, Z, Tewari, A, Immunotherapy in prostate cancer: current state and future perspectives, Ther Adv Urol., 2020, 12, 1756287220951404.
Nair, SS, Weil, R, Dovey, Z, Davis, A, Tewari, AK, The tumor microenvironment and immunotherapy in prostate and bladder cancer, Urologic Clinics of North America, 2020., e17–e54.
Montopoli, M, Zumerle, S, Vettor, R, Rugge, M, Zorzi, M, Catapano, CV, et al, Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532), Annals of Oncology, 2020, 1040–1045.
Vale, CL, Fisher, D, Kneebone, A, Parker, C, Pearse, M, Richaud, P, et al, Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data, Lancet., 2020, 396, 1422–1431.
Conteduca, V, Ku, S-Y, Puca, L, Slade, M, Fernandez, L, Hess, J, et al, SLFN11 expression in advanced prostate cancer and response to platinum-based chemotherapy, Molecular cancer therapeutics, 2020, 1157–1164.
Warrier, VU, Makandar, AI, Garg, M, Sethi, G, Kant, R, Pal, JK, et al, Engineering anti-cancer nanovaccine based on antigen cross-presentation, Biosci Rep., 2019, 39.
Gupta, B, Sadaria, D, Warrier, VU, Kirtonia, A, Kant, R, Awasthi, A, et al, Plant lectins and their usage in preparing targeted nanovaccines for cancer immunotherapy, Semin Cancer Biol., 2022, 80, 87–106.
Dehm, SM, Tindall, DJ, Molecular regulation of androgen action in prostate cancer, J Cell Biochem., 2006, 99, 333–344.
Heinlein, CA, Chang, C, Androgen receptor in prostate cancer, Endocr Rev., 2004, 25, 276–308.
Aurilio, G, Cimadamore, A, Mazzucchelli, R, Lopez-Beltran, A, Verri, E, Scarpelli, M, et al, Androgen receptor signaling pathway in prostate cancer: from genetics to clinical applications, Cells, 2020, 9.
Dorr, RT, Von Hoff, DD, Cisplatin, Cancer Chemotherapy Handbook (Appleton & Lange, Norwalk, CT), 1994, 286-298.
Boulikas, T, Vougiouka, M, Cisplatin and platinum drugs at the molecular level (Review), Oncology Reports, 2003.
Sherman-Baust, CA, Weeraratna, AT, Rangel, LBA, Pizer, ES, Cho, KR, Schwartz, DR, et al, Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells, Cancer Cell. 2003, 377–386.
Baird, RD, Kaye, SB, Drug resistance reversal are we getting closer ?, Eur J Cancer, 2003, 39, 2450–2461.
Azam, S, Hadi, N, Khan, NU, Hadi, SM, Antioxidant and prooxidant properties of caffeine, theobromine and xanthine, Med Sci Monit, 2003, 9, 325–30.
Andrews, KW, Schweitzer, A, Zhao, C, Holden, JM, Roseland, JM, Brandt, M, et al., The caffeine contents of dietary supplements commonly purchased in the US: analysis of 53 products with caffeine-containing ingredients, Anal Bioanal Chem, 2007, 389, 231–239.
Jabir, NR, Islam, MT, Tabrez, S, Shakil, S, Zaidi, SK, Khan, FR, et al, An insight towards anticancer potential of major coffee constituents, Biofactors, 2018, 44, 315–326.
López-Barrera, DM, Vázquez-Sánchez, K, Loarca-Piña, MGF, Campos-Vega, R, Spent coffee grounds, an innovative source of colonic fermentable compounds, inhibit inflammatory mediators in vitro, Food Chem., 2016, 212, 282–290.
Hu, GL, Wang, X, Zhang, L, Qiu, MH, The sources and mechanisms of bioactive ingredients in coffee, Food Funct., 2019, 10, 3113–3126.
Shaposhnikov, S, Hatzold, T, El Yamani, N, et al, Coffee and oxidative stress: a human intervention study, European Journal of Nutrition, 2018, 57(2), 533–544.
Han, Z, Boyle, DL, Chang, L, et al, c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis, J Clin Invest., 2001, 108(1), 73-81.
Sun, Y, Liu, W-Z, Liu, T, Feng, X, Yang, N, Zhou, H-F, Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis, J Recept Signal Transduct Res., 2015, 35, 600–604.
Brozovic, A, Osmak, M, Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance, Cancer Lett., 2007, 251, 1–16.
Abreu-Martin, MT, Chari, A, Palladino, AA, Craft, NA, Sawyers, CL, Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer, Mol Cell Biol., 1999, 19, 5143–5154.
Ikonen, T, Palvimo, JJ, Kallio, PJ, Reinikainen, P, Jänne, OA, Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation, Endocrinology, 1994, 135, 1359–1366.
Karin, M, Nuclear factor-kappaB in cancer development and progression, Nature, 2006, 441, 431–436.
Mendonca, P, Taka, E, Bauer, D, Reams, RR, Soliman, KFA, The attenuating effects of 1,2,3,4,6 penta-O-galloyl-β-d-glucose on pro-inflammatory responses of LPS/IFNγ-activated BV-2 microglial cells through NFƙB and MAPK signaling pathways, Journal of Neuroimmunology, 2018, 43–53.
American Cancer Society (ACS), Cancer Facts and Figures 2022. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf
Erzurumlu, Y, Ballar, P, Androgen mediated regulation of endoplasmic reticulum-associated degradation and its effects on prostate cancer, Sci Rep., 2017, 7, 40719.
Nguyen-Nielsen, M, Borre, M, Diagnostic and therapeutic strategies for prostate cancer, Semin Nucl Med., 2016, 46, 484–490.
Petrylak, DP, The current role of chemotherapy in metastatic hormone-refractory prostate cancer, Urology, 2005, 65, 3–8.
Perdonà, S, Autorino, R, De Placido, S, D’Armiento, M, Gallo, A, Damiano, R, et al, Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial, Lancet Oncol., 2005, 6, 295–300.
Sartini, M, Bragazzi, NL, Spagnolo, AM, Schinca, E, Ottria, G, Dupont, C, et al, Coffee consumption and risk of colorectal cancer: a systematic review and meta-analysis of prospective studies, Nutrients, 2019, 11.
Oh, CC, Jin, A, Yuan, J-M, Koh, W-P, Coffee, tea, caffeine, and risk of nonmelanoma skin cancer in a Chinese population: the Singapore Chinese health study, J Am Acad Dermatol., 2019, 81, 395–402.
Wiltberger, G, Wu, Y, Lange, U, Hau, H-M, Tapper, E, Krenzien, F, et al, Protective effects of coffee consumption following liver transplantation for hepatocellular carcinoma in cirrhosis, Aliment Pharmacol Ther., 2019, 49, 779–788.
Xu, Y, Ho, CT, Amin, SG, Han, C, Chung, FL, Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants, Cancer Res., 1992, 52, 3875–3879.
Iwamoto, H, Izumi, K, Natsagdorj, A, Naito, R, Makino, T, Kadomoto, S, et al, Coffee diterpenes kahweol acetate and cafestol synergistically inhibit the proliferation and migration of prostate cancer cells, Prostate, 2019, 79, 468–479.
Coffee, tea, mate, methylxanthines and methylglyoxal. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 27 February to 6 March 1990. IARC Monogr Eval Carcinog Risks Hum., 1991, 51, 1-513.
Sciuto, R, Festa, A, Rea, S, Pasqualoni, R, Bergomi, S, Petrilli, G, et al, Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial, J Nucl Med., 2002, 43, 79–86.
Nomura, T, Yamasaki, M, Nomura, Y, Mimata, H, Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells, Oncol Rep., 2005, 14, 993–997.
Guo, X, Ma, N, Wang, J, Song, J, Bu, X, Cheng, Y, et al, Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells, BMC Cancer., 2008, 8, 375.
Han, Z, Meng, L, Huang, X, Tan, J, Liu, W, Chen, W, et al, Inhibition of p38 MAPK increases the sensitivity of 5-fluorouracil-resistant SW480 human colon cancer cells to noscapine, Oncol Lett., 2022, 23, 52.
Pereira, L, Igea, A, Canovas, B, Dolado, I, Nebreda, AR, Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK, EMBO Mol Med., 2013, 5, 1759–1774.
Rodríguez-García, ME, Quiroga, AG, Castro, J, Ortiz, A, Aller, P, Mata, F, Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells, Toxicol Sci., 2009, 111, 413–423.
Godwin, P, Baird, AM, Heavey, S, Barr, MP, O’Byrne, KJ, Gately, K, Targeting nuclear factor-kappa B to overcome resistance to chemotherapy, Front Oncol., 2013, 3, 120.
Peng, C, Ouyang, Y, Lu, N, Li, N, The NF-κB signaling pathway, the microbiota, and gastrointestinal tumorigenesis: recent advances, Front Immunol., 2020, 11, 1387.
Yang, Z, Liao, J, Cullen, KJ, Dan, H, Inhibition of IKKβ/NF-κB signaling pathway to improve Dasatinib efficacy in suppression of cisplatin-resistant head and neck squamous cell carcinoma, Cell Death Discov., 2020, 6, 36.
Ryan, S-L, Beard, S, Barr, MP, Umezawa, K, Heavey, S, Godwin, P, et al, Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC, Lung Cancer, 2019, 135, 217–227.
Wang, P, Cui, J, Wen, J, Guo, Y, Zhang, L, Chen, X, Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, Oncol Lett., 2016, 12, 4605–4612.
Qu, K, Lin, T, Wei, J, Meng, F, Wang, Z, Huang, Z, et al, Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells, Nan Fang Yi Ke Da Xue Xue Bao., 2013, 33, 1253–1259.
Barbiero, M, Cirillo, L, Veerapathiran, S, Coates, C, Ruffilli, C, Pines, J, Cell cycle-dependent binding between Cyclin B1 and Cdk1 revealed by time-resolved fluorescence correlation spectroscopy, Open Biol., 2022, 12, 220057.
Sonntag, R, Giebeler, N, Nevzorova, YA, Bangen, J-M, Fahrenkamp, D, Lambertz, D, et al, Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma, Proc Natl Acad Sci U S A., 2018, 115, 9282–9287.
Loukil, A, Cheung, CT, Bendris, N, Lemmers, B, Peter, M, Blanchard, JM, Cyclin A2: At the crossroads of cell cycle and cell invasion. World J Biol Chem., 2015, 6, 346–350.
Mitsiades, N, Kaochar, S, Androgen receptor signaling inhibitors: post-chemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer, Endocr Relat Cancer., 2021, 28, T19–T38.
Liu, C, Armstrong, CM, Ning, S, Yang, JC, Lou, W, Lombard, AP, et al, ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling, Oncogene, 2021, 40, 5379–5392.
Sopo, M, Anttila, M, Hämäläinen, K, Kivelä, A, Ylä-Herttuala, S, Kosma, V-M, et al, Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer, BMC Cancer, 2019;19: 584.