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

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.

Polymersome‐assisted delivery of curcumin: A suitable approach to decrease cancer stemness markers and regulate miRNAs expression in HT29 colorectal cancer cells

“…However, the major problems in the use of curcumin are its low water solubility, poor bioavailability, fast metabolism, imperfect uptake, and weak tissue distribution· On the other hand, the undesirable prognosis of advanced colon cancer, recurrence, and poor response to treatment have caused colon cancer to be still one of the most common cancers around the world Cancer stem‐like cells (CSC) are responsible for resistance to treatments such as chemo/radiotherapy in variety of cancers such as colon cancer . Therefore, cooperating dietary anticancer agents such as curcumin with conventional drugs could trigger CSC apoptosis and harmonize cell surface proteins, which increasing their expression, can develop CSC in clone cancer . On the other hand, many cellular and molecular pathways involved in CRC could be adjusted by modulating miRNAs expression as suggested biomarkers in cellular stemness, and it is clear that dysregulation of miRNAs is responsible for various uncontrolled biological pathways such as cell cycle, apoptosis, cell proliferation, and tumorigenesis .…”

The roles of curcumin in regulating the tumor immunosuppressive microenvironment (Review)

“…Curcumin has been demonstrated to exert specific functions in resensitizing certain types of cancer to chemotherapy, such as colorectal cancer and ovarian cancer. Chemotherapeutic drugs, such as irinotecan, 5-fluorouracil and capecitabine, show a decline in efficacy during colorectal cancer therapy and cancer stem cells (CSCs) are considered to influence this process (51). Curcumin increases the sensitivity of colon cancer cells to capecitabine by inducing apoptosis of CSCs (51).…”

“…Chemotherapeutic drugs, such as irinotecan, 5-fluorouracil and capecitabine, show a decline in efficacy during colorectal cancer therapy and cancer stem cells (CSCs) are considered to influence this process (51). Curcumin increases the sensitivity of colon cancer cells to capecitabine by inducing apoptosis of CSCs (51). In addition, the combination of mitomycin C and curcumin downregulates the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-w and induces the apoptosis of breast CSCs (52).…”

Curcumin and Colorectal Cancer: From Basic to Clinical Evidences

“…Among the proposed mechanisms of action, induction of epithelial apoptosis seems to be the most investigated [12]. Indeed, it has been shown that curcumin can promote the synthesis of proteins related to apoptotic processes and could interplay with the pathways of inflammation-related programmed death [13][14][15][16].On the basis of this, the use of curcumin in chemoprevention and as a complementary treatment of CRC is promising. Herein, we carried out a literature review that aims to summarize the studies investigating the relationship between curcumin and CRC in vitro, animal models, and human trials.…”

“…Among the proposed mechanisms of action, induction of epithelial apoptosis seems to be the most investigated [12]. Indeed, it has been shown that curcumin can promote the synthesis of proteins related to apoptotic processes and could interplay with the pathways of inflammation-related programmed death [13][14][15][16].…”