Abstract
Background5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells.MethodsMTT (3–4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines.ResultsTreatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax.ConclusionMitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.
Highlights
Cancer, a pathology characterized by unchecked division of cells, is one of the fatal diseases with an increasing number of cases all over the world [1]
5-Fluorouracil (5-FU) is a well-known anti-cancer drug commonly used to treat colorectal cancer (CRC); the agent interferes with DNA and RNA to disrupt the metabolism of the uracil, which lead to the breakdown of DNA and apoptosis of the cancer cells
The enzyme binds to voltage-dependent anion channel (VDAC, or porin) in the outer mitochondrial membrane, which results in resistance to chemotherapy by inhibiting glycolysis [10]
Summary
A pathology characterized by unchecked division of cells, is one of the fatal diseases with an increasing number of cases all over the world [1]. Despite substantial progresses in CRC screening measures and treatment, the prognosis of patients with this cancer remains poor, demanding novel therapeutic strategies to manage the disease [4] In this respect, 5-Fluorouracil (5-FU) is a well-known anti-cancer drug commonly used to treat CRC; the agent interferes with DNA and RNA to disrupt the metabolism of the uracil, which lead to the breakdown of DNA and apoptosis of the cancer cells. The enhancement of the Krebs’ cycle activity in turn increases the activity of the electron transfer chain; a function that increases the production of reactive oxygen species with mitochondrial origin, which lead to selective killing of cancer cells [9] The another agent, 3Br-P, acts as a potent inhibitor of hexokinase; an enzyme that is overexpressed in cancer cells and is essential for the metabolism of cancer cells. The present work assessed the anticancer effects of 3Br-P in combined with DCA in a colorectal cancer cell line, HT-29
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