Upregulation of prostaglandin E2 by inducible microsomal prostaglandin E synthase-1 in colon cancer

Purpose@#Prostaglandin E2 (PGE2) is known to promote carcinogenesis and cancer progression in colon cancer. Enzymes involved in the metabolism of PGE2 include cyclooxygenase (COX)-2, microsomal prostaglandin E synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH). The current study aims to determine how PGE2 is expressed by examining patients with colorectal cancer and evaluating colon cancer cells to gain insight into changes in relevant enzymes upon induction of PGE2. @*Methods@#The concentration of PGE2 was measured in tumor tissues and adjacent normal mucosal tissues of 26 patients with colon cancer. The expression of COX-1, COX-2, mPGES-1, and 15-PGDH proteins was measured. The concentration of PGE2 in FET colon cancer cells was measured both in the initial status and after stimulation by tumor necrosis factor (TNF)-α. The expression levels of PGE2-related enzymes were measured as well. @*Results@#There was no significant difference in the average concentration of PGE2, which was measured at 453.1 pg/mL in cancer tissues and 401.2 pg/mL in normal mucosa. Among PGE2-related enzymes, 15-PGDH was expressed at a lower level in tumor cells than in normal mucosa. In colon cancer cells, PGE2 was found to be upregulated upon stimulation by TNF-α, which led to strong induction of mPGES-1 without any change in the expression of COX-2 among the PGE2-related enzymes. @*Conclusion@#These results demonstrated that PGE2 can be induced by stimuli such as TNF-α, and suggest that activation of mPGES-1 is more closely related than that of COX-2 in the induction of PGE2 on colon cancer.

Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea

BACKGROUND: Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs. METHODS: MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv. RESULTS: The overall MICs for delamanid, bedaquiline, and linezolid ranged from ≤0.025 to >1.6 mg/L, ≤0.0312 to >4 mg/L, and ≤0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and -resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid. CONCLUSIONS: We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs.

Management Outcomes of Colonoscopic Perforations Are Affected by the General Condition of the Patients

PURPOSE: The management of a colonoscopic perforation (CP) varies from conservative to surgical. The objective of this study was to evaluate the outcomes between surgical and conservative treatment of patients with a CP. METHODS: From 2003 to 2016, the medical records of patients with CP were retrospectively reviewed. Patients were divided into 2 groups depending on whether they initially received conservative or surgical treatment. RESULTS: During the study period, a total of 48 patients with a CP were treated. Among them, 5 patients had underlying colorectal cancer and underwent emergency radical cancer surgery; these patients were excluded. The mean age of the remaining 43 patients was 64.5 years old, and the most common perforation site was the sigmoid colon (15 patients). The initial conservative care group included 16 patients, and the surgery group included 27 patients. In the conservative group, 5 patients required conversion to surgery (failure rate: 5 of 16 [31.3%]). Of the surgery group, laparoscopic surgery was performed on 19 patients and open surgery on 8 patients, including 2 conversion cases. Major postoperative complications developed in 11 patients (34.4%), and postoperative mortality developed in 4 patients (12.5%). The only predictor for poor prognosis after surgery was a high American Society of Anesthesiologists physical status classification. CONCLUSION: In this study, conservative treatment for patients with a CP had a relatively high failure rate. Furthermore, surgical treatment showed significant rates of complications and mortality, which depended on the general status of the patients.

Surgical Outcomes and Risk Factors in Patients Who Underwent Emergency Colorectal Surgery

PURPOSE: Emergency colorectal surgery has high rates of complications and mortality because of incomplete bowel preparation and bacterial contamination. The authors aimed to evaluate the surgical outcomes and the risk factors for the mortality and the complication rates of patients who underwent emergency surgery to treat colorectal diseases. METHODS: This is a prospective study from January 2014 to April 2016, and the results are based on a retrospective analysis of the clinical results for patients who underwent emergency colorectal surgery at Chosun University Hospital. RESULTS: A total of 99 patients underwent emergency colorectal surgery during the study period. The most frequent indication of surgery was perforation (75.8%). The causes of disease were colorectal cancer (19.2%), complicated diverticulitis (21.2%), and ischemia (27.2%). There were 27 mortalities (27.3%). The major morbidity was 39.5%. Preoperative hypotension and perioperative blood transfusion were independent risk factors for both morbidity and mortality. CONCLUSION: These results revealed that emergency colorectal surgeries are associated with significant morbidity and mortality. Furthermore, the independent risk factors for both morbidity and mortality in such patiients were preoperative hypotension and perioperative transfusion.

Synchronous Primary Anorectal Melanoma and Sigmoid Adenocarcinoma

A primary anorectal malignant melanoma is a rare tumor. Moreover, cases involving a synchronous anorectal melanoma and colon adenocarcinoma are extremely rare. The authors report a case of a synchronous anorectal melanoma and sigmoid adenocarcinoma in an 84-year-old man. The regions of the anorectal melanoma showed melanocytic nevi in the adjacent mucosa of the anal canal and rectum. A dysplastic nevus was also identified in the anal mucosa. This case demonstrates that an anorectal melanoma can arise from pre-existing anorectal melanocytic lesions.

Outcomes and Risk Factors Affecting Mortality in Patients Who Underwent Colorectal Emergency Surgery

PURPOSE: Emergency colorectal surgery has a high risk of mortality and morbidity because of incomplete bowel preparation, bacterial proliferation, and contamination. In this study, we investigated the outcomes and the risk factors affecting mortality in patients who had undergone emergency surgery for the treatment of various colorectal diseases. METHODS: This study is a retrospective analysis of prospectively collected data to survey the clinical results for patients who had undergone emergency colorectal surgery from January 2014 to December 2014. We analyzed various clinicopathologic factors, which were divided into 3 categories: preoperative, intraoperative, and postoperative. RESULTS: A total of 50 patients had undergone emergency colorectal surgery during the time period covered by this study. Among them, 10 patients (20%) died during the postoperative period. A simple linear regression analysis showed that the risk factors for mortality were old age, preoperative hypotension, and a high American Society of Anesthesiologist (ASA) score. Moreover, a multiple linear regression analysis showed a high ASA score and preoperative hypotension to be independent risk factors. CONCLUSION: In this study, emergency colorectal surgery showed a relatively high mortality rate. Furthermore, the independent risk factors for mortality were preoperative hypotension and high ASA score; thus, patients with these characteristics need to be evaluated more carefully and receive better care if the mortality rate is to be reduced.

Right side fixation of sigmoid colon with a hepato-sigmoidocolic fistula in patient with hepatocellular carcinoma and midgut malrotation / 대한외과학회지

The location of the sigmoid colon varies within the abdominal cavity, but its mesocolon is fixed to the left side. Right side fixation of the sigmoid colon is a very rare congenital positional anomaly. In addition, it has been reported that hepatocolic fistula is also a very rare disease that may present lower gastrointestinal bleeding. Here, the authors describe a case of a 71-year-old man who underwent surgery for hepato-sigmoidocolic fistula complicated by hepatocellular carcinoma and the right side fixation of the sigmoid colon.

Giant Ascending Colonic Diverticulum Presenting With Intussusception

Diverticular disease of the colon is a common disease, and its incidence is increasing gradually. A giant colonic diverticulum (GCD) is a rare entity and is defined as a diverticulum greater than 4 cm in size. It mainly arises from the sigmoid colon, and possible etiology is a ball-valve mechanism permitting progressive enlargement. A plain abdominal X-ray can be helpful to make a diagnosis initially, and a barium enema and abdominal computed tomography may confirm the diagnosis. Surgical intervention is a definite treatment for a GCD. We report a case of an ascending GCD presenting with intussusception in a young adult.

Giant Ascending Colonic Diverticulum Presenting With Intussusception

Diverticular disease of the colon is a common disease, and its incidence is increasing gradually. A giant colonic diverticulum (GCD) is a rare entity and is defined as a diverticulum greater than 4 cm in size. It mainly arises from the sigmoid colon, and possible etiology is a ball-valve mechanism permitting progressive enlargement. A plain abdominal X-ray can be helpful to make a diagnosis initially, and a barium enema and abdominal computed tomography may confirm the diagnosis. Surgical intervention is a definite treatment for a GCD. We report a case of an ascending GCD presenting with intussusception in a young adult.

Prognostic Implication of 15-Hydroxyprostaglandin Dehydrogenase Down-Regulation in Patients with Colorectal Cancer

PURPOSE: Prostaglandin (PG) E2 is known to be closely related to cancer progression and is inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). 15-PGDH is shown to have tumor suppressor activity and to be down-regulated in various cancers, including colorectal cancer (CRC). Therefore, we evaluated the expression of 15-PGDH and its prognostic effect in patients with CRC. METHODS: 15-PGDH expression was examined by using immunohistochemistry in 77 patients with CRC. Its prognostic significance was statistically evaluated. RESULTS: Negative 15-PGDH expression was noted in 55.8% of the 77 cases of CRC. 15-PGDH expression showed no correlation with any of the various clinicopathologic parameters. The status of lymph node metastasis, tumor-node-metastasis stages, and pre-operative carcinoembryonic antigen levels showed significant prognostic effect. However, univariate analysis revealed down-regulation of 15-PGDH not to be a predictor of poor survival. The 5-year overall survival rate was 71.7% in the group with positive expression of 15-PGDH and 67.1% in the group with negative expression of 15-PGDH, but this difference was not statistically significant (P = 0.751). CONCLUSION: 15-PGDH was down-regulated in 55.8% of the colorectal cancer patients. However, down-regulation of 15-PGDH showed no prognostic value in patients with CRC. Further larger scale or prospective studies are needed to clarify the prognostic effect of 15-PGDH down-regulation in patients with colorectal cancer.

Prognostic significance of cytosolic phospholipase A2 expression in patients with colorectal cancer / 대한외과학회지

PURPOSE: Cyclooxygenase-2 is believed to be an important enzyme in the pathogenesis of colorectal cancer (CRC). Cytosolic phospholipase A2 (cPLA2), also, have been suggested to be related to the carcinogenesis of CRC. The aim of this study was to investigate cPLA2 expression and its relationship with prognostic significance in CRC. METHODS: Eighty-eight patients with colorectal cancer who underwent curative surgery were enrolled in this study. cPLA2 was examined in 88 primary CRCs by immunohistochemistry and we compared their expression with clinicopathologic findings, recurrence and survival in patients with CRC. RESULTS: The expression of cPLA2 was positive in 54.5% (48/88). The expression of cPLA2 was not correlated with clinicopathologic parameters. However, cPLA2 expression was significantly related with vascular endothelial growth factor expression. Kaplan-Meier analysis didn't show any clinical significance in disease-free survival and overall survival according to cPLA2 expression. CONCLUSION: These results suggest that cPLA2 expression was not associated with the prognosis of CRC. However, further large-scale studies are needed to clarify the prognostic effect of cPLA2 in CRC.

Up-regulation of cyclooxygenase-2-derived prostaglandin E2 in colon cancer cells resistant to 5-fluorouracil / 대한외과학회지

PURPOSE: It has been suggested that constitutive up-regulation of cyclooxygenase (COX)-2 is associated with resistance to apoptosis, increased angiogenesis, and increased tumor invasiveness in various cancers including colon cancer. There are many factors involved in the resistance to 5-fluorouracil (5-FU) in colon cancer. However, little is known about the role of COX-2 in acquired resistance to 5-FU in colon cancer. METHODS: Hence we investigated whether COX-2 contribute to acquired resistance to 5-FU in colon cancer cells, using cytotoxicity assay for cell survival, reverse transcription-polymerase chain reaction (RT-PCR) for vascular endothelial growth factor (VEGF), quantitative RT-PCR for COX-1 and COX-2, and enzyme-linked immunosorbent assay for PGE2. RESULTS: The 5-FU resistant colon cancer cells, SNU-C5/5FUR, showed increased expression of COX-2, prostaglandin E2 (PGE2), and VEGF, compared to its parental cell (SNU-C5). By treatment with meloxicam, the expression of PGE2 and VEGF was reduced significantly in the resistant cells, but not in the parent cells. CONCLUSION: These results demonstrate that COX-2 derived PGE2 is up-regulated and COX-2 inhibitor may have an anti-angiogenic effect in the colon cancer cells resistant to 5-FU.

Impacts of Cytosolic Phospholipase A2, 15-Prostaglandin Dehydrogenase, and Cyclooxygenase-2 Expressions on Tumor Progression in Colorectal Cancer

PURPOSE: In addition to cyclooxygenase-2 (COX-2) which is related to prostaglandin E2 synthesis, other enzymes such as cytosolic phospholipase A2 (cPLA2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH) have been suggested to be related to carcinogenesis of colorectal cancer (CRC). The aim of this study was to investigate the roles of cPLA2, COX-2, mPGES-1, and 15-PGDH in tumor progression. MATERIALS AND METHODS: cPLA2, COX-2, mPGES-1, 15-PGDH, and vascular endothelial growth factor (VEGF) expressions were immunohistochemically examined in 89 CRC, and their expressions were compared with each other or clinicopathologic parameters as well as VEGF as tumor progression parameters. RESULTS: cPLA2 was expressed in 54.5%, COX-2 in 80.5%, mPGES-1 in 96.4%, 15-PGDH in 46.1%, and VEGF in 65.9%. The expression of cPLA2 correlated with VEGF expression. COX-2 expression was correlated with the depth of invasion, tumor stage, cPLA2, and VEGF expressions. Moreover, VEGF revealed the highest expression in the tissues positive for both cPLA2 and COX-2. Furthermore, 15-PGDH expression was inversely correlated with VEGF expression. CONCLUSION: The present study demonstrates that cPLA2 and mPGES-1, in addition to COX-2, are constitutively overexpressed, and that 15-PGDH might be attenuated in colorectal cancer. Furthermore, cPLA2 and 15-PGDH as well as COX-2 could have an important role in tumor progression.

Clinicopathologic Findings of Micropapillary Carcinomas, according to Tumor Size

PURPOSE: Papillary thyroid microcarcinomas (PTMC), which are not palpable and have no clinical symptoms are 1.0 cm or less in diameter. The optimal extent of thyroid tumor resection has been controversial. We investigated clinicopathological findings of PTMC of 5 mm or less in diameter for reasonable therapeutic approach. METHODS: From, Jan. 2002 to Dec. 2006, 366 patients underwent thyroidectomy for thyroid papillary carcinoma at our institution. Among these patients, 62 patients with a mass measuring less than 5 mm and 103 patients with a mass 5 mm to 1.0 cm were selected. We retrospectively reviewed their medical records. RESULTS: There was no significant difference on the clinical characteristics except multifocality. We performed more unilateral lobectomy, near total thyroidectomy with or without neck node dissection in patients with PTMC of less than 5 mm (P=0.13). In permanent biopsy, lymph node metastasis more frequently occurred in patients with PTMC of less than 5 mm (P=0.03). There were no differences in capsular invasion, distant metastasis or recurrence. CONCLUSION: In papillary thyroid microcarcinoma less than 0.5 cm, it is very uncommon for capsular invasion, distant metastasis and locoregional metastasis to exist. The extent of tumor resection may be limited less than near total thyroidectomy for suitable cases, because there was no locoregional metastasis or distant metastasis in the follow-up period. Longer follow-up periods would be required to confirm that limited surgery is sufficient for tumors less than 0.5 cm in size.

The Risk Factors Associated with Surgical Site Infection after an Abdominal Operation

PURPOSE: Surgical site infection (SSI) is the most common nosocomial infection in surgical patients, and this accounts for 38% of all patients with nosocomial infections. Despite the advances in techniques and knowledge to prevent infection, SSI remains a significant source of postoperative morbidity and mortality, and it results in a prolonged hospital stay and increased cost. This study aims to assess the incidence of SSI and to identify the risk factors associated with SSI for patients who undergo abdominal operation. METHODS: The data on 347 abdominal operations that were done under general anesthesia from 1 August 2005 to 31 July 2006 was collected and reviewed. RESULTS: The overall incidence of SSI was 4.9%. Comorbidity was the independent risk factor for the development of SSI (P=0.011). The development of SSI was related with the American Society of Anesthesiologists (ASA) preoperative assessment score (P=0.025). The duration of the operation had a statistically significant association with an increased risk of SSI on univariate analysis. The wound classification was not associated with SSI. Staphylococcus aureus was the most frequently isolated organism, and all of the cases were methcillin-resistant Staphylococcus aureus. CONCLUSION: This study demonstrate that comorbidity is a significant independent risk factor for SSI.

Expression of Vascular Endothelial Growth Factor in Colorectal Cancer

PURPOSE: The neovascularization is an essential factor for the growth of solid organ cancer and especially vascular endothelial growth factor (VEGF) has been known to the very important mediator of neovascularization. Thus, this study was searching that expression of VEGF in colorectal cancer correlate to clinicopathologic factors. METHODS: We analyzed 93 patients with sporadic colorectal cancer who underwent colectomy and their specimens were studied immunohistochemistry at Chosun University hospital from March, 2002 to November, 2005. RESULTS: The expression rate of VEGF was 61 cases of all (65.6%). There were no significant relation VEGF expression to age, sex and lymph node metastasis. But, VEGF expression in colon cancer was 80.5% rather than 53.8% in rectal cancer (P=0.010). Correlation with T staging, expression of VEGF was 10.0% in pT0, 62.5% in pT1, pT2 and 77.2% in pT3, pT4 (P<0.0001), and correlation with TNM staging, expression of VEGF was 10.0% in stage 0, 63.2% in stage I, 72.0% in stage II, 73.3% in stage III and 100.0% in stage IV (P=0.001). CONCLUSIONS: Expression of VEGF in colorectal cancer closely correlates with cancer progression and VEGF was more expressed in colon cancer than rectum.

Recurrent Colonic Perforation after Successful Conservative Treatment of Colonoscopic Perforation

Although the management of a colonic perforation after a colonoscopy is still controversial, conservative therapy is commonly used in those whose colonoscopy reveals a small perforation, those whose condition is relatively good, those who were diagnosed belatedly, or those who have not developed the symptoms of generalized peritonitis. We encountered a case of recurrent colonic perforation after successful conservative treatment for a colonoscopic perforation of the sigmoid colon in a 69-year-old female, who was treated with tube sigmoidostomy.

Expression of Cyclooxygenase-2 and its Relationship to p53 Accumulation in Colorectal Cancers

PURPOSE: Cyclooxygenase (COX)-2 is an inducible isoform responsive to cytokines, mitogens, and growth factors, and is believed to be an important enzyme related to colorectal cancer (CRC). Existing evidence suggests that COX-2 expression is normally suppressed by wild-type p53 but not mutant p53, suggesting that loss of p53 function may result in the induction of COX-2 expression. The aim of this study was to determine the relationship between COX-2 expression and p53 levels in CRC. MATERIALS AND METHODS: Patients with sporadic colorectal adenocarcinoma (n=161) who underwent curative surgery in Chosun University Hospital were enrolled in this study. Expression of COX-2 and p53 proteins was examined by immunohistochemistry in paraffin-embedded cancer tissue blocks, and the relationship between COX-2 and/or p53 expression with clinicopathologic parameters was analyzed. RESUTLS: Expression of COX- 2 was positive in 47.8% of colorectal cancers, and significantly associated with the depth of tumor invasion (p= 0.042). In contrast, p53 was positive in 50.3% of the cases, and was associated with both age (p=0.025) and the depth of tumor invasion (p=0.014). There was no correlation between COX-2 expression and p53 expression (p=0.118). CONCLUSION: These results suggest that COX-2 expression might play an important role in the progression of colorectal cancer. However, COX-2 expression was not associated with mutational p53. Further studies are needed to clarify the regulatory mechanisms governing COX-2 overexpression in colorectal cancers.

Adjuvant Effect of NSAIDs on the Cytotoxicity of Colon Cancer Cells to 5-FU

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, is believed to be an important enzyme related to colorectal cancer. A large number of studies have supported the concept that non-steroidal anti-inflammatory drugs (NSAIDs) targeting COX alter the biologic processes of colon carcinogenesis. Although COX-2 inhibitors generally reduce the growth rate of established tumors, tumor regression is rarely observed. Hence, it is reasonable that COX-2 inhibitors be given in conjunction with standard anti-cancer therapy in treating cancer. We investigated whether aspirin and meloxicam not only are cytotoxic but also potentiate the antitumor effect of 5-Fluorouracil (5-FU) against colon cancer cells. METHODS: Expressions of COX-1 and COX-2 were determined by using the reverse transcriptase-polymerase chain reaction (RT-PCR) & Western blotting assay in 9 colon cancer cell lines. The cytotoxicities of NSAIDs and/or 5-FU were determined by using a microculture tetrazolium dye (MTT) assay. RESULTS: COX-1 mRNA and protein, as well as COX-2 mRNA, were variably expressed in all the cell lines tested whereas COX-2 protein was expressed in HT-29 and to a lesser extent in HCT-8, but not in the other cell lines. We selected two representative cell lines, HT-29 expressing COX-2 protein and SNU-C1 not expressing it. The dose-dependent cytotoxicity was observed in both cell lines treated with aspirin and with meloxicam. A combination treatment of aspirin or meloxicam with 5-FU revealed some additive effect, rather than a synergistic effect, for both cells lines. This additive effect was remarkable even for low concentrations of the drugs. Furthermore, the additive effect was highest when the combination was adminstered sequentially, 5-FU followed by aspirin or meloxicam, in both cell lines. CONCLUSIONS: These results suggest that a combination therapy using NSAIDs and 5-FU might be useful in the treatment of colon cancer cells not expressing COX-2, as well as in colon cancer cells expressing COX-2.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells. METHODS: Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry. RESULTS: Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP. CONCLUSIONS: This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines.