Prostate cancer presents a significant global health challenge, often exhibiting resistance to chemotherapy drugs and causing severe side effects from conventional treatments. These side effects include toxicity to normal cells and mineral deficiencies, which can lead to complications such as acute diarrhea, electrolyte imbalances, and chemotherapy-induced peripheral neuropathy. Natural compounds like curcumin offer promising synergistic anticancer properties with relatively low toxicity and can reduce co-delivered drug resistance. Concurrently, concentrated marine mineral (CMM) solutions, rich in essential minerals, are being explored as adjunct therapies to mitigate chemotherapy-induced mineral deficiencies and potentially enhance curcumin’s efficacy and uptake. This study evaluates the comparative cytotoxic effects of curcumin, CMM, and their combination against DU145 prostate cancer cells and HEK293 normal kidney cells, using cisplatin as a benchmark. Curcumin and CMM demonstrate potent inhibition of DU145 cells, classifying them as highly active while showing reduced cytotoxicity towards HEK293 cells compared to cisplatin. Combining curcumin and CMM enhances cytotoxicity against prostate cancer cells while mitigating toxicity to normal cells. Moreover, the combined treatment effectively downregulates Cyclin-D1, Wnt3a, and C-Myc expression in prostate cancer cells, with optimal effects observed at a 5 ppm curcumin and 5 ppm CMM ratio. These results underscore the potential of curcumin and CMM as a synergistic therapeutic strategy for prostate cancer, offering enhanced efficacy and reduced side effects compared to conventional cisplatin chemotherapy.
Alaydrus S, Sriwidodo S, Diantini A, Amalia R, Wahyuni W, Wulandari A. Downregulation of Cyclin-D, Wnt3a, and C-Myc in prostate cancer by dose-dependent combination of concentrated marine minerals and curcumin. J Appl Pharm Sci. 2025. Article in Press. http://doi.org/10.7324/JAPS.2025.217025
1. Barsouk A, Padala SA, Vakiti A, Mohammed A, Saginala K, Thandra KC, et al. Epidemiology, staging and management of prostate cancer. Med Sci. 2020 Jul 20;8(3):28. https://doi.org/10.3390/medsci8030028
2. James ND, Tannock I, N’Dow J, Feng F, Gillessen S, Ali SA, et al. The Lancet Commission on prostate cancer: planning for the surge in cases. Lancet. 2024 Apr;403(10437):1683-722. https://doi.org/10.1016/S0140-6736(24)00651-2
3. Kalathil AA, Guin S, Ashokan A, Basu U, Surnar B, Delma KS, et al. New pathway for cisplatin prodrug to utilize metabolic substrate preference to overcome cancer intrinsic resistance. ACS Cent Sci. 2023 Jul 26;9(7):1297-312. https://doi.org/10.1021/acscentsci.3c00286
4. Catapano J, Luty M, Wróbel T, Pude?ek M, Piwowarczyk K, K?dracka-Krok S, et al. Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress. Cell Mol Biol Lett. 2022 Dec 18;27(1):100. https://doi.org/10.1186/s11658-022-00400-1
5. Nakazawa M, Paller C, Kyprianou N. Mechanisms of therapeutic resistance in prostate cancer. Curr Oncol Rep. 2017 Feb 22;19(2):13. https://doi.org/10.1007/s11912-017-0568-7
6. Jernberg E, Bergh A, Wikström P. Clinical relevance of androgen receptor alterations in prostate cancer. Endocr Connect. 2017 Nov;6(8):R146-61. https://doi.org/10.1530/EC-17-0118
7. Le TK, Duong QH, Baylot V, Fargette C, Baboudjian M, Colleaux L, et al. Castration-resistant prostate cancer: from uncovered resistance mechanisms to current treatments. Cancers (Basel). 2023 Oct 19;15(20):5047. https://doi.org/10.3390/cancers15205047
8. Arnold JT, Isaacs JT. Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell’s fault. Endocr Relat Cancer. 2002 Mar;9(1):61-73. https://doi.org/10.1677/erc.0.0090061
9. Das S. Phytochemicals modify the action of cancer cells mitochondrial drug-resistance mechanism. Sci Pharm. 2023 Jul 14;2(3):79-105. https://doi.org/10.58920/sciphar02030079
10. Mathur A, Abd Elmageed ZY, Liu X, Kostochka ML, Zhang H, Abdel-Mageed AB, et al. Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells. PLoS One. 2014 Aug 14;9(8):e103109. https://doi.org/10.1371/journal.pone.0103109
11. Shankar S, Chen Q, Sarva K, Siddiqui I, Srivastava RK. Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal. 2007 Oct 4;2:10. https://doi.org/10.1186/1750-2187-2-10
12. Deeb D, Xu YX, Jiang H, Gao X, Janakiraman N, Chapman RA, et al. Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells. Mol Cancer Ther. 2003 Jan;2(1):95-103.
13. Deeb D, Jiang H, Gao X, Hafner MS, Wong H, Divine G, et al. Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol Cancer Ther. 2004 Jul;3(7):803-12. https://doi.org/10.1158/1535-7163.803.3.7
14. Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene. 2004 Feb 26;23(8):1599-607. https://doi.org/10.1038/sj.onc.1207284
15. Ide H, Lu Y, Yamaguchi R, Muto S, Horie S. Abstract 226: Chemopreventive potential of curcumin in prostate cancer. Cancer Res. 2014 Oct 1;74(19_Supplement):226. https://doi.org/10.1158/1538-7445.AM2014-226
16. Pan L, Sha J, Lin W, Wang Y, Bian T. Curcumin inhibits prostate cancer progression by regulating the miR 30a 5p/PCLAF axis. Exp Ther Med. 2021 Jul 7;22(3):969. https://doi.org/10.3892/etm.2021.10401
17. Venturelli S, Leischner C, Helling T, Renner O, Burkard M, Marongiu L. Minerals and cancer: overview of the possible diagnostic value. Cancers (Basel). 2022 Feb 28;14(5):1256. https://doi.org/10.3390/cancers14051256
18. Ames BN, Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002 Sep;2(9):694-704. https://doi.org/10.1038/nrc886
19. Wesselink E, Winkels R, Van Baar H, Geijsen A, Van Zutphen M, Van Halteren H, et al. Dietary intake of magnesium or calcium and chemotherapy-induced peripheral neuropathy in colorectal cancer patients. Nutrients. 2018 Mar 23;10(4):398. https://doi.org/10.3390/nu10040398
20. Workeneh BT, Uppal NN, Jhaveri KD, Rondon-Berrios H. Hypomagnesemia in the cancer patient. Kidney360. 2021 Jan;2(1):154-66. https://doi.org/10.34067/KID.0005622020
21. Mohd Nani SZ, Majid FAA, Jaafar AB, Mahdzir A, Musa MN. Potential health benefits of deep sea water: a review. Evidence-Based Complement Altern Med. 2016;2016:1-18. https://doi.org/10.1155/2016/6520475
22. Kim S, Chun SY, Lee DH, Lee KS, Nam KS. Mineral-enriched deep-sea water inhibits the metastatic potential of human breast cancer cell lines. Int J Oncol. 2013 Nov;43(5):1691-700. https://doi.org/10.3892/ijo.2013.2089
23. Kotagale NR, Charde PB, Helonde A, Gupta KR, Umekar MJ, Raut NS. Studies on bioavailability enhancement of curcumin. Int J Pharm Pharm Sci. 2020 Feb; 12(2):20-5. https://doi.org/10.22159/ijpps.2020v12i2.36027
24. Sriwidodo, Abd. Kakhar Umar, Ega Megawati, Maria Elvina Tresia Butarbutar, Nasrul Wathoni, Syafika Alaydrus. Physicochemical characterization of concentrated mineral and magnesium isolate of sea water pamekasan madura. Int J Res Pharm Sci. 2020 Dec 21;11(SPL4):2154-7. https://doi.org/10.26452/ijrps.v11iSPL4.4436
25. Alaydrus S, Umar AK, Sriwidodo S, Diantini A, Wathoni N, Amalia R. Characterization and acute oral toxicity of concentrated minerals of Pamekasan Madura seawater. J Adv Pharm Technol Res [Internet]. 2021;12(3):305-9. https://doi.org/10.4103/japtr.JAPTR_250_20
26. Jiang X, Li S, Qiu X, Cong J, Zhou J, Miu W. Curcumin inhibits cell viability and increases apoptosis of SW620 human colon adenocarcinoma cells via the caudal type homeobox-2 (CDX2)/ Wnt/β-catenin pathway. Med Sci Monit. 2019;25. https://doi.org/10.12659/MSM.918364
27. Takeuchi Y, Tanegashima T, Sato E, Irie T, Sai A, Itahashi K, et al. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. Sci Immunol. 2022;6(65):eabc6424. https://doi.org/10.1126/sciimmunol.abc6424
28. Gusungi DE, Maarisit W, Hariyadi H, Potalangi NO. Studi Aktivitas Antioksidan Dan Antikanker Payudara (MCF-7) Ekstrak Etanol Daun Benalu Langsat Dendrophthoe pentandra. Biofarmasetikal Trop. 2020 May 11;3(1):166-74. https://doi.org/10.55724/j.biofar.trop.v3i1.274
29. Indrayanto G, Putra GS, Suhud F. Validation of in-vitro bioassay methods: Application in herbal drug research. Profiles Drug Subst Excip Relat Methodol. 2021;46:273-307. https://doi.org/10.1016/bs.podrm.2020.07.005
30. Awan A, Basulaiman B, Stober C, Clemons M, Fergusson D, Hilton J, et al. Oral magnesium supplements for cancer treatment-induced hypomagnesemia: results from a pilot randomized trial. Heal Sci Reports. 2021 Dec 14;4(4):e443. https://doi.org/10.1002/hsr2.443
31. Oronsky B, Caroen S, Oronsky A, Dobalian VE, Oronsky N, Lybeck M, et al. Electrolyte disorders with platinum-based chemotherapy: mechanisms, manifestations and management. Cancer Chemother Pharmacol. 2017 Nov 20;80(5):895-907. https://doi.org/10.1007/s00280-017-3392-8
32. Ezoe Y, Mizusawa J, Katayama H, Kataoka K, Muto M. An integrated analysis of hyponatremia in cancer patients receiving platinum-based or nonplatinum-based chemotherapy in clinical trials (JCOG1405-A). Oncotarget. 2018 Jan 19;9(5):6595-606. https://doi.org/10.18632/oncotarget.23536
33. Kulkarni S, Bhandary D, Singh Y, Monga V, Thareja S. Boron in cancer therapeutics: an overview. Pharmacol Ther. 2023 Nov;251:108548. https://doi.org/10.1016/j.pharmthera.2023.108548
34. Scorei RI, Popa R. Boron-containing compounds as preventive and chemotherapeutic agents for cancer. Anticancer Agents Med Chem. 2010 May 1;10(4):346-51. https://doi.org/10.2174/187152010791162289
35. Robbins D, Zhao Y. Manganese superoxide dismutase in cancer prevention. Antioxid Redox Signal. 2014 Apr;20(10):1628-45. https://doi.org/10.1089/ars.2013.5297
36. Wang Y, Zhong D, Xie F, Chen S, Ma Z, Yang X, et al. Manganese phosphate-doxorubicin-based nanomedicines using mimetic mineralization for cancer chemotherapy. ACS Biomater Sci Eng. 2022 May 9;8(5):1930-41. https://doi.org/10.1021/acsbiomaterials.2c00011
37. Abdel-Tawab M. Considerations to be taken when carrying out medicinal plant research-what we learn from an insight into the IC50 values, bioavailability and clinical efficacy of exemplary anti-inflammatory herbal components. Pharmaceuticals. 2021 May 6;14(5):437. https://doi.org/10.3390/ph14050437
38. Aldossary SA. Review on pharmacology of cisplatin: clinical use, toxicity and mechanism of resistance of cisplatin. Biomed Pharmacol J. 2019 Mar 28;12(1):07-15. https://doi.org/10.13005/bpj/1608
39. Hayati F, Hossainzadeh M, Shayanpour S, Abedi-Gheshlaghi Z, Beladi Mousavi SS. Prevention of cisplatin nephrotoxicity. J Nephropharmacology. 2016;5(1):57-60.
40. Mohammadi K, Thompson KH, Patrick BO, Storr T, Martins C, Polishchuk E, et al. Synthesis and characterization of dual function vanadyl, gallium and indium curcumin complexes for medicinal applications. J Inorg Biochem. 2005 Nov;99(11):2217-25. https://doi.org/10.1016/j.jinorgbio.2005.08.001
41. Pucci D, Bellini T, Crispini A, D’Agnano I, Liguori PF, Garcia- Orduña P, et al. DNA binding and cytotoxicity of fluorescent curcumin-based Zn(ii) complexes. Medchemcomm. 2012;3(4):462. https://doi.org/10.1039/c2md00261b
42. Ferrari E, Benassi R, Sacchi S, Pignedoli F, Asti M, Saladini M. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications. J Inorg Biochem. 2014 Oct;139:38-48. https://doi.org/10.1016/j.jinorgbio.2014.06.002
43. Liao DJ, Thakur A, Wu J, Biliran H, Sarkar FH. Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit Rev Oncog. 2007;13(2):93-158. https://doi.org/10.1615/CritRevOncog.v13.i2.10
44. Montalto FI, De Amicis F. Cyclin D1 in Cancer: a molecular connection for cell cycle control, adhesion and invasion in tumor and stroma. Cells. 2020 Dec 9;9(12):2648. https://doi.org/10.3390/cells9122648
45. Kypta RM, Waxman J. Wnt/β-catenin signalling in prostate cancer. Nat Rev Urol. 2012 Aug 19;9(8):418-28. https://doi.org/10.1038/nrurol.2012.116
46. Truica MI, Burns MC, Han H, Abdulkadir SA. Turning up the heat on MYC: progress in small-molecule inhibitors. Cancer Res. 2021 Jan 15;81(2):248-53. https://doi.org/10.1158/0008-5472.CAN-20-2959
Year
Month