Abstract
Celastrol (tripterine) a pentacyclic triterpenoid extracted from the roots of Tripterygium wilfordii Hook f., exhibits potent antioxidant and anti-inflammatory activity and also exerts important anti-cancer effects, as induction of apoptosis and lowering the level of drug resistance of several cancers.Increased level of cellular resistance to cytostatic drugs is typical for colorectal cancers, and largely determines the failure of chemotherapy for this tumor.The purpose of our research was to evaluate the chemopreventive effect of celastrol on cultures of colon cancer cells resistant to doxorubicin (LOVO/DX). With the use of flow cytometry we have shown that celastrol reduces the cell size of the SP (side population; subpopulation of cancer cells enriched with cancer stem cells), increases frequency of apoptosis and binds to Pgp protein in cell membranes inhibiting its transport function. The inhibition of the Pgp transport function has been shown to increase the accumulation of rhodamine-123 and standard cytostatic- doxorubicin in LOVO/DX cells.Our results prove that celastrol exhibits significant chemopreventive and chemosensitizing activities on drug resistant colon cancer cells. Celastrol appears to be a good candidate for adjuvant medicine that can improve the effectiveness of standard cytostatic therapy in humans.
Highlights
Colon cancer is the third most common form of cancer and the second leading cause of cancer-related death in western countries [1]
With the use of flow cytometry we have shown that celastrol reduces the cell size of the Side Population (SP), increases frequency of apoptosis and binds to Pgp protein in cell membranes inhibiting its transport function
We have examined chemopreventive effect of celastrol on drug resistant colon cancer cells, including its impact on functional/transporter activity of the glycoprotein P (P-gp), on frequency of apoptosis and necrosis in colon cancer cell cultures, as well as on size of the SP cells subpopulation
Summary
Colon cancer is the third most common form of cancer and the second leading cause of cancer-related death in western countries [1]. The novel treatment strategies are needed to overcome or evade the drug-resistance of colon cancer. In order to improve the outcomes of colon cancer treatment, attention is paid to the role of cancer stem cells (CSCs) in the development of drug resistance status of the tumor. Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, drug and radiation resistance, invasive growth, metastasis, and tumor relapse, which are the main causes of cancer-related deaths [4]. CSCs play an important role in recurrence of colon cancer following chemotherapy, because of their resistance to cytostatic drugs and the ability to unlimited proliferation and self-renewal [9]. The main mechanism of the development of colon cancer cells drug-resistance is the overexpression of glycoprotein P (P-gp). This protein, encoded by the ABCB1 [multidrug resistance protein 1 (MDR1)] gene, belongs to the family of ATP-dependent transporters (ABC transporters), which actively removes the chemotherapeutic drugs from cancer cells [10, 11]
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