Biomedical subjects

Y Kakehi

Publications and source records attributed to Y Kakehi.

At least 19 recordsLinked to original sources

PubMed1996

Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: evidence of persistent oxidative stress in cancer.

Data regarding oxidatively modified DNA bases suggest that cancer cells are more exposed to oxidative stress than adjacent non-tumorous tissue. This novel concept may contribute to the understanding of certain aspects of tumor biology such as activated transcription factors, genetic instability, chemotherapy-resistance and metastasis. We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTH1, an enzyme preventing the misincorporation into DNA of 8-oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool. The expression of hMTH1 messenger RNA (mRNA) in RCC was significantly higher than that in adjacent non-tumorous kidney. Moreover, advanced-stage tumors showed significantly higher hMTH1 mRNA expression than early-stage tumors, and there was a modest linear correlation between hMTH1 expression and c-myc expression. The results provide logical support for the concept of "persistent oxidative stress in cancer" and suggest a role of hMTH1 mRNA level as a prognostic marker.

Bacterial Proteins↗

PubMed1996

Expression of multidrug resistance-related genes (mdrl, MRP, GST-pi and DNA topoisomerase II) in urothelial cancers.

OBJECTIVE: To characterize the multidrug resistance (MDR) phenotype in human urothelial cancers, the expression levels of four MDR-related genes (multidrug resistance, mdrl; multidrug resistance-associated protein, MRP; glutathione S-transferase-pi, GST-pi; and DNA topoisomerase II, topo II) were analysed in urothelial cancers. MATERIALS AND METHODS: Fifty-two tumour tissue and three normal urothelial mucosa samples were obtained from 44 patients with urothelial cancers. The expression of each gene was analysed with a reverse-transcription polymerase chain reaction (RT-PCR) method using beta 2-microglobulin (b2m) mRNA as an endogenous control. Levels of expression were expressed as the ratio of the specific products of the target gene to those specific to b2m. RESULTS: In primary urothelial cancer tissues, the mean (SD) expression of mdrl, MRP, GST-pi and topo II relative to b2m expression were 0.067 (0.061), 0.27 (0.23), 0.35 (0.31) and 0.12 (0.05), respectively. The mean expressions of MRP and GST-pi were higher than those of mdrl and topo II. The mean ratios of mdrl/b2m, MRP/b2m, GST-pi/b2m and topo II/b2m in normal urothelial mucosa were 0.06 (0.03), 0.12 (0.09), 0.30 (0.32) and 0.14 (0.01), respectively. There was no significant association of the expression of each gene with either the grade or extent of the primary tumour. The level of MRP expression in each sample was correlated significantly with the expression of mdrl and GST-pi in the urothelial cancers (r = 0.637 and 0.537, respectively). Chemotherapy did not markedly influence the induction of expression of the MDR-related genes, except for one case in which mdrl expression was 15 times greater than before chemotherapy. The expression of GST-pi in the patients not receiving chemotherapy was significantly higher than in those that did. CONCLUSIONS: These results suggest that the activation of MRP and GST-pi expression occurs during the tumorigenesis of urothelial cancers and that it may confer de novo and acquired drug resistance on urothelial cancers. These results should provide further insight into the complex role postulated for MDR-related genes in chemotherapy, carcinogenesis and tumour progression.

DNA Topoisomerases, Type II↗

PubMed1996

Expression patterns of multidrug-resistance (MDR1), multidrug resistance-associated protein (MRP),glutathione-S-transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) genes in renal cell carcinomas and normal kidney.

PURPOSE: Expression levels of the multidrug-resistance (mdr1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) genes in normal kidney and renal cell carcinomas were analyzed to study the complexity of the roles of these genes. MATERIALS AND METHODS: The reverse transcription-polymerase chain reaction (RT-PCR) assay was used with beta 2 microglobulin (beta 2 m) as the internal control. RESULTS: In normal kidneys, the expression levels of the 4 genes in individual normal kidney samples correlated significantly with one another. Comparisons of the expression levels between normal kidneys and renal cell carcinomas showed that only the mean MRP gene expression level was higher in renal cell carcinomas than in normal kidneys (p = 0.018). The expression patterns of the 4 genes in renal cell carcinomas differed markedly for nonpapillary and papillary tumors. The mean MRP/beta 2 m ratio for the papillary type was significantly lower than that for the nonpapillary alveolar type carcinoma (p = 0.004). The 4 genes showed moderate positive correlations with one another in alveolar type renal carcinoma similar to the correlations observed in normal kidneys. In contrast, in papillary type, MRP expression was inversely correlated with mdr1 and Topo II expression. CONCLUSION: Differences in cytogenetic changes, origins and natural histories between papillary and nonpapillary carcinoma may be associated with these distinct expression patterns of the resistance-related genes. Further study is required to clarify whether the differences in the expression patterns between these 2 structural types of carcinoma affect their chemosensitivities and clinical outcomes.

ATP-Binding Cassette Transporters↗

PubMed1996

Immunocytochemical detection of p53 in cultures of exfoliated cells from urine of patients with urothelial cancers.

Early diagnosis of urothelial cancer is critical for successful treatment. Mutation of the p53 gene together with allelic loss of chromosome 17p correlates well with high grade and invasiveness of urothelial cancer. Moreover, this mutation is reported to be an early event for carcinoma in situ of the urothelium. In order to develop a new non-invasive diagnostic method for urothelial cancer, we have established a short-term culture system for urinary exfoliated cells from patients with urothelial cancer. Immunocytochemical detection of p53 in these urine-derived cells was conducted. Short-term cultures of exfoliated cells from 50 ml samples of urine from 52 patients with urothelial cancers were made. Adequate cell growth (> 10(5) cells per flask) was followed by passage onto glass chamber slides for p53 immunocytochemical staining. Successful passage was obtained in 40 of the 52 (76.9%) patients with urothelial cancers studied. The success rate for patients with tumors immunohistochemically positive for p53 nuclear accumulation was 90.5%, and 61.3% for those with tumors negative for p53 (P < 0.05). Results of immunochemical analysis of the p53 in the urine cells and those in the tumor samples were identical in 92.1% of the patients. Culture of exfoliated cells from urine would be a good, non-invasive method for the molecular diagnosis of urothelial cancer that should prove useful for the early detection and follow-up of tumors with p53 mutation.

Adult↗

PubMed1996

Equivalent parental distribution of frequently lost alleles and biallelic expression of the H19 gene in human testicular germ cell tumors.

Epigenetic alterations such as genomic imprinting might play an important role in human tumorigenesis, in addition to specific genetic alterations. To clarify the role of genetic and/or epigenetic alterations in the tumorigenesis of testicular germ cell tumors (GCTs), we analyzed 40 primary and 3 metastatic testicular GCTs with regard to specific chromosomal losses and their parental origin. A high incidence of loss of heterozygosity (LOH) was demonstrated on chromosomes 1p, 3p, 11p, and 17p: 9/19 (47%), 18/39 (46%), 13/40 (33%) and 20/36 (56%), respectively. However, there was no correlation between the frequency of LOH on any chromosome and clinicopathological features. Regarding the parental origin of the lost allele at these chromosomes, preferential loss was not demonstrated in this study. To clarify the imprinting status in GCTs, we analyzed the allele-specific expression of the H19 gene, which is paternally imprinted on chromosome 11p. All of 11 tumors without LOH at this locus showed biallelic expression of H19. Based on previous work demonstrating the biallelic expression of H19 in primordial germ cells and spermatogonia in the mouse germ line, these results suggest that the biallelic expression of H19 in testicular GCTs reflects the characteristics of the original germ cells in which the imprinting marking has been erased and not established, rather than loss of imprinting during tumorigenesis. It is also possible that a failure to re-establish the imprinting might be an initial event which leads to testicular GCTs.

Alleles↗

PubMed1996

Simultaneous left renal pelvic and bilateral ureteral tumors producing carbohydrate antigen 19-9.

We report a case of a transitional cell carcinoma of the left renal pelvis and both ureters which secreted carbohydrate antigen 19-9. Aggressive surgery was performed including a left nephroureterectomy including the bladder cuff and a right total ureterectomy with an ileal graft replacement. The patient has had good kidney function and no evidence of disease for one year postoperatively.

Aged↗

PubMed1996

Management of late complications of continent urinary diversion using the Kock pouch and the Indiana pouch procedures.

BACKGROUND: Continent urinary diversion (CUD) is performed on patients after total cystourethrectomy due to invasive bladder cancer or other diseases requiring urinary diversion. Since 1984, we have performed CUD using either the Kock pouch procedure or a modified Indiana pouch method. During the long-term follow-up, increasing numbers of late complications occurred, especially after the Kock pouch procedure. We summarized the frequency of postoperative complications, their management, and outcome of CUD using these 2 methods. METHODS: Between 1984 and 1995, CUD using the Kock pouch method was performed on 102 patients, and on 61 patients using the Indiana pouch method, with a mean follow-up period of 83 and 50 months, respectively. The patients were between 24 and 82 years old, with a mean age of 59 years. In most patients, the Kock pouch was constructed according to the original method, except for the use of a Dacron fabric collar, and the Indiana pouch was made using the ileal patch method. RESULTS: Of 95 patients followed up for more than 3 months after CUD using the Kock pouch method, efferent and afferent nipple valve malfunction occurred in 21 (22%) and 26 (27%) patients, respectively. Efferent complications occurred during the first year after surgery, whereas afferent complications occurred several years after surgery. Open repair surgery (excluding ileus) was necessary for 36 (38%) patients. Of 59 patients followed for more than 3 months after CUD using the Indiana pouch method, 7 patients with stomal stenosis, 2 patients with stomal prolapse, and 1 patient with stricture at the ureterocolonic anastomosis were treated surgically. An hourglass-like deformity of the pouch was seen in 2 patients, on whom the original Indiana pouch method was performed. As a whole, 13 patients (22%) were retreated with open surgery. Urinary calculi occurred in 42 (44%) patients after CUD using the Kock pouch method and in 11 patients (19%) using the Indiana pouch method. The outcome was excellent, good, fair, and poor in 31, 37, 24, and 8% of the patients after CUD using the Kock pouch method, and in 36, 17, 42, and 5% of the patients after CUD using the Indiana pouch method. CONCLUSIONS: We performed CUD using either the Kock pouch or the Indiana pouch method with a success rate of approximately 90%. The rates of revision, reoperation and stone formation were higher with the Kock pouch procedure than with the Indiana pouch procedure, while varying degrees of incomplete incontinence and difficulty in catheterization were seen more often in the latter.

Adult↗

PubMed1996

Urinary calculi as a late complication of the Indiana continent urinary diversion: comparison with the Kock pouch procedure.

PURPOSE: Although urinary calculi have been frequent late complications of the Kock continent urinary diversion, they have not been regarded as significant problems in patients with the Indiana pouch because of the lack of foreign material present. However, stones developed in a significant percentage of our patients with an Indiana pouch. We investigated the characteristics of stone formation in patients with the Indiana pouch and compared them to those with a Kock pouch. MATERIALS AND METHODS: Detailed clinical courses regarding stone formation were reviewed in 72 patients with a Kock pouch and 54 with an Indiana pouch who had a minimum followup of 12 months. RESULTS: Stones developed in 7 of 54 patients (12.9%) with an Indiana pouch compared to 31 of 72 (43.1%) with a Kock pouch. The incidence gradually increased with longer followup but it was lower in the Indiana than in the Kock pouch group (5-year stone-free rate 84% versus 66%, respectively). Although the stones consisted principally of a mixture of struvite, carbonate apatite and ammonium hydrogen urate, variable amounts of calcium oxalate were identified in 50% of the Indiana pouch calculi. CONCLUSIONS: Not only urinary infections but also metabolic factors were considered to be involved in stone formation within the Indiana pouch. However, the substantially higher rate of stone formation in our Kock and Indiana pouch groups than has been reported in the United States suggested that no or infrequent pouch irrigations in our patients were important risk factors for urinary calculi.

Case-Control Studies↗

PubMed1996

[Asynchronous metastases solely to the bilateral adrenal glands from bladder cancer: a case report].

We report a case of transitional cell carcinoma of the bladder metastasizing to bilateral adrenal glands without other metastasis. A 47-year-old male underwent total cystectomy due to bladder cancer (TCC, G2, pT2) in 1992. One year later, CT scan showed a large tumor in the right adrenal gland. Right adrenalectomy revealed metastatic transitional cell carcinoma. He underwent 3 courses of M-VAC postoperatively. However, one year after the second operation, left adrenal tumor was detected by CT. Because there was no apparent metastasis other than the adrenal gland, left adrenalectomy was performed and the tumor was transitional cell carcinoma of grade 3. He was discharged from the hospital after 2 courses of CISCA chemotherapy, and has been doing well without evidence of recurrence for two years, being supported by the adrenocortical steroids.

Adrenal Gland Neoplasms↗

PubMed1996

[A case of localized amyloidosis of the ureter].

A case of localized amyloidosis of the ureter is reported. The patient was a 49-year-old female whose chief complaint was macrohematuria. Roentogenographic examination showed left hydronephrosis due to stenosis of left middle ureter. Left nephrouretectomy with cuff was performed with a diagnosis of the left ureteral tumor, and pathological examination revealed localized amyloidosis of the left ureter. Localized amyloidosis of the ureter is a rare lesion, and this is the twenty-first case reported in the Japanese literature. Review of the literature revealed that it is difficult to differentiate this lesion from other ureteral tumors by roentgenographic examination, and it is important to perform preoperative or intraoperative biopsy of ureteral tumors if benign diseases cannot be ruled out.

Amyloidosis↗

PubMed1995

Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma.

Mitogen-activated protein kinases (MAPKs) play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAPK cascade, which includes MEK (also known as MAP kinase kinase), Raf-1, and Ras. In this study, we examined whether constitutive activation of the MAPK cascade was associated with the carcinogenesis of human renal cell carcinomas in a series of 25 tumors and in corresponding normal kidneys. Constitutive activation of MAPKs in tumor tissue, as determined by the appearance of phosphorylated forms, was found in 12 cases (48%), and this activation was confirmed by a direct in vitro kinase assay of immunoprecipitate using myelin basic protein as the substrate. The phosphorylation of MEK and of Raf-1, as monitored by a mobility shift in SDS-PAGE, which is reportedly associated with the activation of these kinases, occurred in 9 of 18 cases (50%) and in 6 of 11 cases (55%) respectively. The activation of MAPKs was correlated with MEK activation (P = 0.0045) and with Raf-1 activation (P = 0.067). Furthermore, overexpression of MEK was found in 13 of 25 cases (52%) by Western blot analysis, and this overexpression was associated significantly with MAPK activation (P = 0.034). No mutations were noted in H-,K-, or N-ras genes by PCR direct sequencing in any of the 25 tumor samples. Of the patients studied, 8 of 18 (44%) stage pT2 patients and four of six (67%) stage pT3 patients showed MAPK activation. The single stage pT1 patient did not evidence MAPK activation. Furthermore, one of seven (14%) grade 1 patients, 9 of 13 (69%) grade 2 patients, and two of five (40%) grade 3 patients showed MAPK activation (grade 1 versus grades 2 and 3, P = 0.046). Our results suggest that constitutive activation of MAPKs may be associated with the carcinogenesis of human RCCs.

Amino Acid Sequence↗

PubMed1995

Allelic frequency of p53 gene codon 72 polymorphism in urologic cancers.

Alterations in the p53 tumor suppressor gene appear to be important in the development of many human tumors. The wild-type p53 gene has a polymorphism at codon 72 that presents the arginine (CGC) or proline (CCC) genotype, which recently has been reported to be associated with genetically determined susceptibility to smoking-related lung cancers. To determine whether this p53 genotype influences individual risk of urologic cancer and/or its progression, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis to assay the allelic frequencies of this polymorphism in 85 renal cell carcinoma patients, 151 urothelial cancer patients, 33 testicular cancer patients, 28 prostatic cancer patients and 56 patients without neoplastic disease. The allelic distributions of the three genotypes (Arg/Arg, Arg/Pro, Pro/Pro) in patients with renal cell carcinoma (29.4%, 55.3%, 15.3%), urothelial cancers (45.7%, 39.7%, 14.6%), testicular cancer (45.4%, 48.5%, 6.1%) or prostate cancer (42.9%, 50.0%, 7.1%) did not differ significantly from those in the normal controls. However, Pro/Pro genotype in renal cell carcinoma and urothelial cancer (smoking-related cancers) was more frequent than that in prostate cancer and testicular cancer (smoking-unrelated cancers) with borderline significance (P = 0.0881). There was no particular correlation between frequency of the three genotypes and grade or stage of each type of tumor. The association of genetic predisposition to urologic cancers with p53 gene codon 72 polymorphism is not so clear as the previous study of Japanese lung cancer patients, but this polymorphism may play some role in urothelial cancers and renal cell carcinoma, in which smoking is an epidemiological risk factor.

Adult↗

PubMed1995

Multidrug resistance-associated protein-mediated multidrug resistance modulated by cyclosporin A in a human bladder cancer cell line.

A doxorubicin-resistant subline (5637/DR5.5) from human bladder cancer cells (5637) was induced by stepwise increase in the doxorubicin concentration. 5637/DR5.5 cells were cross-resistant to vinblastine and etoposide but not to mitomycin C and cisplatin. We analyzed the mdr1, MRP (multidrug resistance-associated protein), and DNA topoisomerase II gene expression using the reverse transcription polymerase chain reaction assay (RT-PCR) and investigated possible differences in the accumulation and efflux of radiolabeled daunorubicin. 5637/DR5.5 cells do not express the mdr1 gene, but the expression levels of MRP are markedly higher than in drug-sensitive 5637 cells. The intracellular accumulation of radiolabeled daunorubicin was markedly decreased in the 5637/DR5.5 cells in comparison with the parent cells. This reduced drug accumulation was associated with an enhanced drug efflux, but was reversed when cells were incubated with cyclosporin A. Cyclosporin A at the concentration of 5 microM caused 3.4-fold enhancement of daunorubicin-sensitivity in the 5637/DR5.5 cells. On the other hand, there was no difference in DNA-topoisomerase II activity between the parent and resistant cells. The resistance of the 5637/DR5.5 cells is therefore associated with an enhanced drug efflux mediated by the MRP gene overexpression, as distinct from P-glycoprotein, and is modulated by cyclosporin A.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

Contribution of chromosome 9p21-22 deletion to the progression of human renal cell carcinoma.

To investigate the possible role of genomic aberrations of chromosome 9p21-22 in the tumorigenesis of human renal cell carcinoma (RCC), 10 RCC cell lines, 55 primary RCCs and 5 metastatic lesions were studied by Southern blotting and polymerase chain reaction-based analysis. Nine of 10 RCC cell lines showed a homozygous deletion of MTSI/CDKN2/(p16), while only 1 in 55 primary tumors had this deletion. Loss of heterozygosity on 9p21-22 was observed in 5 of 10 informative primary RCCs from patients with metastasis, but in only 4 of 31 informative tumors (13%) without metastasis (P = 0.025). Futhermore, 3 of 5 metastatic tumors (60%) showed hemi- or homozygous deletion of MTSI/CDKN2. These results indicate that the 9p21-22 deletion may be a relatively late event in RCC tumorigenesis and could be associated with RCC metastasis.

Alleles↗

PubMed1995

Basic research.

Basic research is currently investigating the molecular cascade associated with bladder cancer development. Many new findings are potential leads towards the improvement of the diagnosis and prognosis of this disease. Special care, however, should be taken in the design of protocols for clinical evaluation of the value of these markers. Some initial guidelines have been put forward in this report.

Alleles↗

PubMed1995

Serum granulocyte colony-stimulating factor levels in patients with urinary bladder tumour and various urological malignancies.

OBJECTIVES: To measure the serum levels of granulocyte colony-stimulating factor (G-CSF) in patients with urinary bladder tumour (UBT) or various urological malignant tumours, and to assess G-CSF production by tumour cells. PATIENTS AND METHODS: Peripheral blood was obtained, before operation or anti-cancer therapy, from 141 patients with UBT, 37 patients with other urological malignant tumours (21 with renal cell carcinoma, nine with renal pelvic or ureteric tumours, five with prostatic cancer, and two with testicular cancer), 38 patients with benign urological diseases (21 with benign prostatic hypertrophy, 11 with urolithiasis and six with a varicocele), and from 15 healthy donors. The serum G-CSF levels were quantified using an enzyme immunoassay. RESULTS: Of 141 patients with UBT, 13 showed elevated serum G-CSF levels above the sensitivity of the assay (30 pg/mL) with a mean value of 328 pg/mL. The serum levels in normal healthy donors and in patients with prostatic cancer, testicular cancer or varicocele were < 30 pg/mL, while the levels were > 30 pg/mL in two of nine patients with renal pelvic or ureteric tumour (mean 754 pg/mL) and in one of 21 patients with renal cell carcinoma (40 pg/mL). The levels of serum G-CSF in several patients with benign prostatic hypertrophy or urolithiasis were also elevated, but the mean levels were low. The serum G-CSF levels in patients with UBT correlated with the increase of grade and the progression of the stage of UBT. Furthermore, patients with UBT and an undetectable level of serum G-CSF had higher disease-specific survival rates at the 5-year follow-up when compared with those with an elevated level of serum G-CSF. There was a positive correlation between serum G-CSF levels and white blood cell counts. T24 and J82 UBT cell lines and freshly separated tumour cells derived from the patient whose serum G-CSF level was high produced G-CSF. CONCLUSION: These results suggest that elevated serum G-CSF level might be associated with a poor prognosis in patients with UBT and be due to the production of G-CSF by UBT cells.

Adult↗

PubMed1995

[E-cadherin expression and histopathological features in renal cell carcinomas].

E-cadherin, a member of the cadherin family, plays a major role in cell-cell adhesion of normal epithelium. Recent studies have demonstrated that heterogeneous expression, reduction or loss of E-cadherin is involved in invasion and metastasis of cancer cells. In this study, the localization of E-cadherin in the normal human kidney and the relationship between E-cadherin expression and histopathological features in renal cell carcinomas was examined immunohistochemically. Renal cell carcinoma tissues and normal kidney counterparts were obtained from 20 patients. E-cadherin in the normal kidney was detected in the cell-cell border of the distal tubules, collecting duct and Bowman's capsule but not in the proximal tubules. E-cadherin expression was reduced in all the clear cell type renal cell carcinomas with compact or cystic configuration (n = 15), while it was well preserved in all the papillary type (n = 3) and chromophobe cell type (n = 1) renal cell carcinomas. Different expression patterns between primary site and metastasis, i.e., homogeneously weak in primary tumor and heterogeneously positive in metastatis, was observed in a case of clear cell type renal cell carcinoma. Different patterns of expression between clear and non-clear cell type, or between papillary and non-papillary type, together with strong expression in chromophobe type might reflect the origin of each type of renal cell carcinoma. Further studies will clarify whether the change in expression of E-cadherin is associated with the prognosis of renal cell carcinoma.

Adult↗

PubMed1995

Cepharanthin, a multidrug resistant modifier, is a substrate for P-glycoprotein.

P-glycoprotein modulators are respected to be multidrug resistance reversing agents in cancer chemotherapy. Some calcium channel blockers, calmodulin inhibitors or immunosuppressive agents have been used in clinical studies, although the dose of these drugs required to test in vitro experimental data might cause potent pharmacological effects which are not desirable in patients. By using LLC-GA5-COL150 cells that express P-glycoprotein specifically on the apical membranes, we examined the transport of anticancer drugs mediated by P-glycoprotein. Cepharanthin, a biscoclaurine alkaloid, potently inhibits the transport of vinblastine and daunorubicin, both commonly used anticancer agents. The 50% inhibitory concentration of cepharanthin on daunorubicin transport was 2.06 microM. Combined inhibitory effects on daunorubicin transport were observed when cepharanthin was used together with cyclosporin A, a potent immunosuppressive agent and P-glycoprotein modulator. Cepharanthin itself was transported by P-glycoprotein. Transcellular transport of cepharanthin across LLC-GA5-COL150 cell monolayers was saturable when its concentration was under 5 microM, and the transport was inhibited by P-glycoprotein modulators. These results indicate that cepharanthin can reverse multidrug resistance, and proper combination with other P-glycoprotein modulators could potentiate its inhibitory effect on expelling the anticancer drugs out of the cell via P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗