Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells

Su,Pengfei; Yang,Yong; Wang,Guoxin; Chen,Xiaowu; Ju,Yongle

doi:10.3892/ijo.2018.4461

Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells

Authors:
- Pengfei Su
- Yong Yang
- Guoxin Wang
- Xiaowu Chen
- Yongle Ju
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China, Department of General Surgery, Heping Hospital Affiliated with Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
Published online on: June 29, 2018 https://doi.org/10.3892/ijo.2018.4461
Pages: 1343-1353

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Resistance to conventional chemotherapeutic agents, including irinotecan (CPT‑11), 5-fluorouracil and capecitabine is a major cause for therapeutic failure in patients with colorectal cancer (CRC). Increasing evidence has demonstrated that cancer cells exhibiting stem cell-like characteristics are associated with the development of resistance to chemotherapeutic agents. As a plant polyphenol, curcumin has been demonstrated to have the ability to ameliorate resistance of CRC to chemotherapeutic agents, but the associations among curcumin, cancer stem cells (CSCs) and chemoresistance of CRC remain unclear. The present study established a CPT‑11-resistant colon cancer cell line, LoVo/CPT‑11 cells, and detected the expression levels of CSC identification markers [cluster of differentiation (CD)44, CD133, epithelial cell adhesion molecule (EpCAM) and CD24] in parental cells and CPT‑11-resistant cells. It was revealed that the expression levels of the colon CSC markers in LoVo/CPT‑11 cells were significantly higher compared those in parental cells at the mRNA and protein level. The effect of curcumin on the chemoresistance to CPT‑11 and the expression levels of CSC identification markers in LoVo/CPT‑11 cells separately treated with curcumin and CPT‑11 were further investigated. The results revealed that curcumin significantly attenuated chemoresistance to CPT‑11, and treatment with curcumin resulted in a significant reduction of the expression levels of CSC identification markers. Furthermore, a tumor sphere formation assay was used to enrich colon CSCs from LoVo/CPT‑11 cells, and demonstrated that curcumin efficiently diminished the traits of colon CSCs, as evidenced by the inability to form tumor spheres, the reduction in the expression of CSC identification markers, and apoptosis-induced effects on sphere-forming cells treated with curcumin alone or in combination with CPT‑11. Altogether, the present data demonstrated that curcumin attenuated resistance to chemotherapeutic drugs through induction of apoptosis of CSCs among colon cancer cells. These findings may provide novel evidence for the therapeutic application of curcumin in CRC intervention.

View Figures

View References

1	Armelao F and de Pretis G: Familial colorectal cancer: A review. World J Gastroenterol. 20:9292–9298. 2014.PubMed/NCBI
2	James MI, Iwuji C, Irving G, Karmokar A, Higgins JA, Griffin-Teal N, Thomas A, Greaves P, Cai H, Patel SR, et al: Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett. 364:135–141. 2015. View Article : Google Scholar : PubMed/NCBI
3	Lam AK, Chan SS and Leung M: Synchronous colorectal cancer: Clinical, pathological and molecular implications. World J Gastroenterol. 20:6815–6820. 2014. View Article : Google Scholar : PubMed/NCBI
4	Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, Jemal A, Cho H, Anderson RN, Kohler BA, et al: Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 120:1290–1314. 2014. View Article : Google Scholar
5	Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland CR and Goel A: Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 36:355–367. 2015. View Article : Google Scholar : PubMed/NCBI
6	Fan X, Zhang C, Liu DB, Yan J and Liang HP: The clinical applications of curcumin: Current state and the future. Curr Pharm Des. 19:2011–2031. 2013.
7	Wang J, Zhu R, Sun D, Sun X, Geng Z, Liu H and Wang SL: Intracellular uptake of curcumin-loaded solid lipid nanoparticles exhibit anti-inflammatory activities superior to those of curcumin through the NF-kB signaling pathway. J Biomed Nanotechnol. 11:403–415. 2015. View Article : Google Scholar : PubMed/NCBI
8	Jin H, Qiao F, Wang Y, Xu Y and Shang Y: Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathway. Oncol Rep. 34:2782–2789. 2015. View Article : Google Scholar : PubMed/NCBI
9	Sobolewski C, Muller F, Cerella C, Dicato M and Diederich M: Celecoxib prevents curcumin-induced apoptosis in a hematopoietic cancer cell model. Mol Carcinog. 54:999–1013. 2015. View Article : Google Scholar
10	Liao H, Wang Z, Deng Z, Ren H and Li X: Curcumin inhibits lung cancer invasion and metastasis by attenuating GLUT1/MT1-MMP/MMP2 pathway. Int J Clin Exp Med. 8:8948–8957. 2015.PubMed/NCBI
11	Shehzad A, Qureshi M, Anwar MN and Lee YS: Multifunctional curcumin mediate multitherapeutic effects. J Food Sci. 82:2006–2015. 2017. View Article : Google Scholar : PubMed/NCBI
12	Yallapu MM, Jaggi M and Chauhan SC: Curcumin nano-medicine: A road to cancer therapeutics. Curr Pharm Des. 19:1994–2010. 2013.
13	Zhu JY, Yang X, Chen Y, Jiang Y, Wang SJ, Li Y, Wang XQ, Meng Y, Zhu MM, Ma X, et al: Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and Sonic Hedgehog pathways. Phytother Res. 31:680–688. 2017. View Article : Google Scholar : PubMed/NCBI
14	Mukherjee S, Mazumdar M, Chakraborty S, Manna A, Saha S, Khan P, Bhattacharjee P, Guha D, Adhikary A, Mukhjerjee S, et al: Curcumin inhibits breast cancer stem cell migration by amplifying the E-cadherin/β-catenin negative feedback loop. Stem Cell Res Ther. 5:1162014. View Article : Google Scholar
15	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar
16	Taniguchi H, Moriya C, Igarashi H, Saitoh A, Yamamoto H, Adachi Y and Imai K: Cancer stem cells in human gastrointestinal cancer. Cancer Sci. 107:1556–1562. 2016. View Article : Google Scholar : PubMed/NCBI
17	Bitarte N, Bandres E, Boni V, Zarate R, Rodriguez J, Gonzalez-Huarriz M, Lopez I, Javier Sola J, Alonso MM, Fortes P, et al: MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells. 29:1661–1671. 2011. View Article : Google Scholar : PubMed/NCBI
18	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
19	Wu S, Wang X, Chen J and Chen Y: Autophagy of cancer stem cells is involved with chemoresistance of colon cancer cells. Biochem Biophys Res Commun. 434:898–903. 2013. View Article : Google Scholar : PubMed/NCBI
20	Yang Y, Wang G, Zhu D, Huang Y, Luo Y, Su P, Chen X and Wang Q: Epithelial-mesenchymal transition and cancer stem cell-like phenotype induced by Twist1 contribute to acquired resistance to irinotecan in colon cancer. Int J Oncol. 51:515–524. 2017. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
22	Botchkina G: Colon cancer stem cells - from basic to clinical application. Cancer Lett. 338:127–140. 2013. View Article : Google Scholar
23	Elshamy WM and Duhé RJ: Overview: Cellular plasticity, cancer stem cells and metastasis. Cancer Lett. 341:2–8. 2013. View Article : Google Scholar : PubMed/NCBI
24	Yoshida GJ and Saya H: Therapeutic strategies targeting cancer stem cells. Cancer Sci. 107:5–11. 2016. View Article : Google Scholar :
25	Stavrovskaya AA and Stromskaya TP: Transport proteins of the ABC family and multidrug resistance of tumor cells. Biochemistry (Mosc). 73:592–604. 2008. View Article : Google Scholar
26	Dandawate PR, Subramaniam D, Jensen RA and Anant S: Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol. 40–41:192–208. 2016. View Article : Google Scholar : PubMed/NCBI
27	Chang TC, Yeh CT, Adebayo BO, Lin YC, Deng L, Rao YK, Huang CC, Lee WH, Wu AT, Hsiao M, et al: 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype. Toxicol Appl Pharmacol. 288:258–268. 2015. View Article : Google Scholar : PubMed/NCBI
28	Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 104:10158–10163. 2007. View Article : Google Scholar : PubMed/NCBI
29	Sanders MA and Majumdar AP: Colon cancer stem cells: Implications in carcinogenesis. Front Biosci. 16:1651–1662. 2011. View Article : Google Scholar
30	Nautiyal J, Kanwar SS, Yu Y and Majumdar AP: Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal. 6:72011. View Article : Google Scholar : PubMed/NCBI
31	Hong SP, Wen J, Bang S, Park S and Song SY: CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer. 125:2323–2331. 2009. View Article : Google Scholar : PubMed/NCBI
32	Ma S: Biology and clinical implications of CD133(+) liver cancer stem cells. Exp Cell Res. 319:126–132. 2013. View Article : Google Scholar
33	Zhang SS, Han ZP, Jing YY, Tao SF, Li TJ, Wang H, Wang Y, Li R, Yang Y, Zhao X, et al: CD133(+)CXCR4(+) colon cancer cells exhibit metastatic potential and predict poor prognosis of patients. BMC Med. 10:852012. View Article : Google Scholar : PubMed/NCBI
34	Cui S and Chang PY: Current understanding concerning intestinal stem cells. World J Gastroenterol. 22:7099–7110. 2016. View Article : Google Scholar : PubMed/NCBI
35	Khan MI, Czarnecka AM, Helbrecht I, Bartnik E, Lian F and Szczylik C: Current approaches in identification and isolation of human renal cell carcinoma cancer stem cells. Stem Cell Res Ther. 6:1782015. View Article : Google Scholar : PubMed/NCBI
36	Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A and Gholamin M: Isolation, identification, and characterization of cancer stem cells: A review. J Cell Physiol. 232:2008–2018. 2017. View Article : Google Scholar
37	Cai J, Peng T, Wang J, Zhang J, Hu H, Tang D, Chu C, Yang T and Liu H: Isolation, culture and identification of choriocarcinoma stem-like cells from the human choriocarcinoma cell-line JEG-3. Cell Physiol Biochem. 39:1421–1432. 2016. View Article : Google Scholar : PubMed/NCBI
38	Moghbeli M, Moghbeli F, Forghanifard MM and Abbaszadegan MR: Cancer stem cell detection and isolation. Med Oncol. 31:692014. View Article : Google Scholar : PubMed/NCBI
39	Shaheen S, Ahmed M, Lorenzi F and Nateri AS: Spheroid-formation (colonosphere) assay for in iitro assessment and expansion of stem cells in colon cancer. Stem Cell Rev. 12:492–499. 2016. View Article : Google Scholar : PubMed/NCBI
40	Ning X, Du Y, Ben Q, Huang L, He X, Gong Y, Gao J, Wu H, Man X, Jin J, et al: Bulk pancreatic cancer cells can convert into cancer stem cells (CSCs) in vitro and 2 compounds can target these CSCs. Cell Cycle. 15:403–412. 2016. View Article : Google Scholar
41	Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G and Wicha MS: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 122:777–785. 2010. View Article : Google Scholar
42	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
43	Pozzi V, Sartini D, Rocchetti R, Santarelli A, Rubini C, Morganti S, Giuliante R, Calabrese S, Di Ruscio G, Orlando F, et al: Identification and characterization of cancer stem cells from head and neck squamous cell carcinoma cell lines. Cell Physiol Biochem. 36:784–798. 2015. View Article : Google Scholar : PubMed/NCBI
44	Roy S, Lu K, Nayak MK, Bhuniya A, Ghosh T, Kundu S, Ghosh S, Baral R, Dasgupta PS and Basu S: Activation of D₂ dopamine receptors in CD133+ve cancer stem cells in non-small cell lung carcinoma inhibits proliferation, clonogenic ability, and invasiveness of these cells. J Biol Chem. 292:435–445. 2017. View Article : Google Scholar
45	Taylor RC, Cullen SP and Martin SJ: Apoptosis: Controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 9:231–241. 2008. View Article : Google Scholar
46	Gupta S, Kass GE, Szegezdi E and Joseph B: The mitochondrial death pathway: A promising therapeutic target in diseases. J Cell Mol Med. 13:1004–1033. 2009. View Article : Google Scholar : PubMed/NCBI
47	Zhang L, Huo X, Liao Y, Yang F, Gao L and Cao L: Zeylenone, a naturally occurring cyclohexene oxide, inhibits proliferation and induces apoptosis in cervical carcinoma cells via PI3K/AKT/mTOR and MAPK/ERK pathways. Sci Rep. 7:16692017. View Article : Google Scholar : PubMed/NCBI
48	Martinou JC and Youle RJ: Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 21:92–101. 2011. View Article : Google Scholar : PubMed/NCBI
49	Adan A, Alizada G, Kiraz Y, Baran Y and Nalbant A: Flow cytometry: Basic principles and applications. Crit Rev Biotechnol. 37:163–176. 2017. View Article : Google Scholar
50	Keyvani-Ghamsari S, Rabbani-Chadegani A, Sargolzaei J and Shahhoseini M: Effect of irinotecan on HMGB1, MMP9 expression, cell cycle, and cell growth in breast cancer (MCF-7) cells. Tumour Biol. 39:1010428317698354. 2017. View Article : Google Scholar : PubMed/NCBI
51	Rudolf E, John S and Cervinka M: Irinotecan induces senescence and apoptosis in colonic cells in vitro. Toxicol Lett. 214:1–8. 2012. View Article : Google Scholar : PubMed/NCBI
52	Ogden A, Rida PC, Reid MD, Kucuk O and Aneja R: Die-hard survivors: Heterogeneity in apoptotic thresholds may underlie chemoresistance. Expert Rev Anticancer Ther. 15:277–281. 2015. View Article : Google Scholar : PubMed/NCBI
53	Spangle JM, Roberts TM and Zhao JJ: The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta. 1868:123–131. 2017.PubMed/NCBI
54	Daaboul HE, Daher CF, Bodman-Smith K, Taleb RI, Shebaby WN, Boulos J, Dagher C, Mroueh MA and El-Sibai M: Antitumor activity of β-2-himachalen-6-ol in colon cancer is mediated through its inhibition of the PI3K and MAPK pathways. Chem Biol Interact. 275:162–170. 2017. View Article : Google Scholar : PubMed/NCBI
55	Yu ST, Zhong Q, Chen RH, Han P, Li SB, Zhang H, Yuan L, Xia TL, Zeng MS and Huang XM: CRLF1 promotes malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways. Cell Death Dis. 9:3712018. View Article : Google Scholar : PubMed/NCBI
56	Zhou Q, Chen J, Feng J, Xu Y, Zheng W and Wang J: SOSTDC1 inhibits follicular thyroid cancer cell proliferation, migration, and EMT via suppressing PI3K/Akt and MAPK/Erk signaling pathways. Mol Cell Biochem. 435:87–95. 2017. View Article : Google Scholar : PubMed/NCBI
57	Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, Rodriguez S, et al: PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 30:2547–2557. 2011. View Article : Google Scholar : PubMed/NCBI
58	Lin L, Liu Y, Li H, Li PK, Fuchs J, Shibata H, Iwabuchi Y and Lin J: Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030. Br J Cancer. 105:212–220. 2011. View Article : Google Scholar : PubMed/NCBI