Curcumin Analogs, PGV-1 and CCA-1.1 Exhibit Anti-migratory Effects and Suppress MMP9 Expression on WiDr Cells

Febri Wulandari, Muthi' Ikawati, Mitsunori Kirihata, Jun-Ya Kato, Edy Meiyanto


BACKGROUND: Colon cancer is still a crucial concern in the development of chemotherapeutic drugs due to the drug resistance phenomenon and various side effects to patients. One of the newest compound that show anticancer activities against several cancer cells, Chemoprevention Curcumin Analog 1 (CCA-1.1), has increasingly been explored to overcome the limitation of conventional drugs.

METHODS: We evaluated the anti-migratory effect of CCA-1.1 and Pentagamavunone-1 (PGV-1) by using WiDr colon cancer cells. The expression profiles of Tumor Protein 53 (TP53) and Matrix Metalloproteinase-9 (MMP9) in colon cancer were obtained from the UALCAN database. Survival outcomes of TP53 and MMP9 in colon cancer patients were analyzed using the Kaplan-Meier method. We used 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), scratch wound healing, and gelatin zymography assays to observe the cytotoxic effect, anti-migratory activity, and MMP9 expression, respectively, in CCA-1.1 or PGV-1-treated cells.

RESULTS: Level of MMP9 was found significantly overexpressed in the primary tumor and metastasis nodal, while TP53 mutation sample types were observed and influenced the survival outcome in colon cancer patients. CCA-1.1 and PGV-1 exhibited strong cytotoxic activity after 24 and 48 h treatment against WiDr cells. The migration assay demonstrated that PGV-1 and CCA-1.1 at 1 mM inhibited cell migration up to 40% after 48 h in single and combination with doxorubicin. The MMP9 expression was significantly inhibited by 0.5 mM CCA-1.1.

CONCLUSION: This study emphasizes that the anti-migratory effect of CCA-1.1 is better than PGV-1 via MMP9 suppression on WiDr. Thus, CCA-1.1 is prominent to be developed as an anti-metastatic agent.

KEYWORDS: chemopreventive curcumin analog 1.1 (CCA-1.1), PGV-1, WiDr cells, anti-migration, MMP9

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Novitasari D, Wulandari F, Jenie RI, Utomo RY, Kato JY, Meiyanto E. A new curcumin analog, CCA-1.1, induces cell cycle arrest and senescence toward ER-positive breast cancer cells. Int J Pharm Sci Res. 2021; 13: 9, CrossRef.

Novitasari D, Jenie RI, Wulandari F, Utomo RY, Putri DDP, Kato JY, et al. A curcumin like structure (CCA-1.1) induces permanent mitotic arrest (senescence) on triple negative breast cancer (TNBC) cells, 4T1. Res J Pharm Sci. 2021; in press.

Wulandari F, Ikawati M, Meiyanto E, Kirihata M, Hermawan A. Bioinformatic analysis of CCA-1.1, a novel curcumin analog, uncovers furthermost noticeable target genes in colon cancer. Gene Rep. 2020; 21: 100917, article.

Wulandari F, Utomo RY, Novitasari D, Ikawati M, Kirihata M, Kato JY, et al. The anti-migratory activity of a new curcumin analog, CCA-1.1, against T47D breast cancer cells. Int J Pharm Sci Res. 2021; 13: 2877-87, CrossRef.

Nguyen H, Duong H. The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review). Oncol Lett. 2018; 16: 9-18, CrossRef.

García-Aranda M, Redondo M. Targeting Receptor Kinases in Colorectal Cancer. Cancers. 2019 Mar 27;11(4):433, CrossRef.

Solé X, Crous-Bou M, Cordero D, Olivares D, Guinó E, Sanz-Pamplona R, et al. Discovery and validation of new potential biomarkers for early detection of colon cancer. PLoS ONE. 2014; 9: e106748, CrossRef.

De Angelis PM, Svendsrud DH, Kravik KL, Stokke T. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006; 5: 20, CrossRef.

Jin J, Wu X, Yin J, Li M, Shen J, Li J, et al. Identification of genetic mutations in cancer: challenge and opportunity in the new era of targeted therapy. Front Oncol. 2019; 9: 263, CrossRef.

Li H, Zhang J, Tong JHM, Chan AWH, Yu J, Kang W, et al. Targeting the oncogenic p53 mutants in colorectal cancer and other solid tumors. IJMS. 2019; 20: 5999, CrossRef.

Noguchi P, Wallace R, Johnson J, Earley EM, O’Brien S, Ferrone S, et al. Characterization of WiDr: a human colon carcinoma cell line. In Vitro. 1979; 15: 401-8, CrossRef.

Said A, Raufman JP, Xie G. The role of matrix metalloproteinases in colorectal cancer. Cancers. 2014; 6: 366-75, CrossRef.

Utami DT, Nugraheni N, Jenie RI, Meiyanto E. Co-treatment of brazilein enhances cytotoxicity of doxorubicin on WiDr colorectal cancer cells through cell cycle arrest. Indones Biomed J. 2020; 12: 376-83, CrossRef.

Pretzsch E, Bösch F, Neumann J, Ganschow P, Bazhin A, Guba M, et al. Mechanisms of metastasis in colorectal cancer and metastatic organotropism: hematogenous versus peritoneal spread. J Oncol. 2019; 2019: 7407190, CrossRef.

Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, et al. TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy. Br J Cancer. 2009; 100: 1330-5, CrossRef.

Meiyanto E, Septisetyani EP, Larasati YA, Kawaichi M. Curcumin analog pentagamavunon-1 (PGV-1) sensitizes Widr cells to 5-fluorouracil through inhibition of NF-κB activation. Asian Pac J Cancer Prev. 2018; 19: 49-56, CrossRef.

Meiyanto E, Putri H, Larasati YA, Utomo RY, Jenie RI, Ikawati M, et al. Anti-proliferative and anti-metastatic potential of curcumin analogue, pentagamavunon-1 (PGV-1), toward highly metastatic breast cancer cells in correlation with ROS generation. Adv Pharm Bull. 2019; 9: 445-52, CrossRef.

Meiyanto E, Husnaa U, Kastian RF, Putri H, Larasati1 YA, Khumaira A, et al. The target differences of anti-tumorigenesis potential of curcumin and its analogues against HER-2 positive and triple-negative breast cancer cells. Adv Pharm Bull. 2021; 11: 188-96, CrossRef.

Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017; 19: 649-58, CrossRef.

Utomo RY, Wulandari F, Novitasari D, Lestari B, Susidarti RA, Jenie RI, et al. Preparation and cytotoxic evaluation of PGV-1 derivative, CCA-1.1, as a new curcumin analog with improved-physicochemical and pharmacological properties. Adv Pharm Bull. 2021; in press, article.

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65: 55-63, CrossRef.

Ahlina FN, Nugraheni N, Salsabila IA, Haryanti S, Da’i M, Meiyanto E. Revealing the reversal effect of galangal (Alpinia galanga L.) extract against oxidative stress in metastatic breast cancer cells and normal fibroblast cells intended as a co-chemotherapeutic and anti-ageing agent. Asian Pac J Cancer Prev. 2020; 21: 107-17, CrossRef.

Nakayama M, Oshima M. Mutant p53 in colon cancer. J Mol Cell Biol. 2019; 11: 267-76, CrossRef.

Guntarno NC, Rahaju AS, Kurniasari N. The role of MMP-9 and VEGF in the invasion state of bladder urothelial carcinoma. Indones Biomed J. 2021; 13: 61-7, CrossRef.

Meteoglu I, Erdogdu IH, Tuncyurek P, Coskun A, Culhaci N, Erkus M, et al. Nuclear factor kappa B, matrix metalloproteinase-1, p53, and Ki-67 expressions in the primary tumors and the lymph node metastases of colorectal cancer cases. Gastroenterol Res Pract. 2015; 2015: 945392, CrossRef.

Blaj C, Schmidt EM, Lamprecht S, Hermeking H, Jung A, Kirchner T, et al. Oncogenic effects of high MAPK activity in colorectal cancer mark progenitor cells and persist irrespective of RAS mutations. Cancer Res. 2017; 77: 1763-74, CrossRef.

Cohen M, Wuillemin C, Irion O, Bischof P. Regulation of MMP-9 by p53 in first trimester cytotrophoblastic cells. Hum Reprod. 2008; 23: 2273-81, CrossRef.

Zhang S, Wu M, Zhao Y, Gu R, Peng C, Liu J, et al. Correlation of MMP-9 and p53 protein expression with prognosis in metastatic spinal tumor of lung cancer. Oncol Lett. 2017; 14: 5452-6, CrossRef.

Xiong S, Xiao GW. Reverting doxorubicin resistance in colon cancer by targeting a key signaling protein, steroid receptor coactivator. Exp Ther Med. 2018; 15: 3751-8, CrossRef.

Amalina N, Nurhayati IP, Meiyanto E. Doxorubicin induces lamellipodia formation and cell migration. Indones J Cancer Chemoprev. 2017; 8: 61-7, CrossRef.

Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors. 2018; 18: 3249, CrossRef.

Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp. 2014; 88: 51046, CrossRef.

Burgos-Morón E, Calderón-Montaño JM, Salvador J, Robles A, López-Lázaro M. The dark side of curcumin. Int J Cancer. 2010; 126: 1771-5, CrossRef.

Aravind SR, Krishnan LK. Curcumin-albumin conjugates as an effective anti-cancer agent with immunomodulatory properties. Int Immunopharmacol. 2016; 34: 78-85, CrossRef.

Darwish S, Mozaffari S, Parang K, Tiwari R. Cyclic peptide conjugate of curcumin and doxorubicin as an anticancer agent. Tetrahedron Letters. 2017; 58: 4617-22, CrossRef.

Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv. 2016; 2: e1501240, CrossRef.

Tan BL, Norhaizan ME. Curcumin combination chemotherapy: the implication and efficacy in cancer. Molecules. 2019; 24: 2527, CrossRef.

Lestari B, Nakamae I, Yoneda-Kato N, Morimoto T, Kanaya S, Yokoyama T, et al. Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Sci Rep. 2019; 9: 14867, CrossRef.


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