Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein-protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages.

Detailed resume of RNA m6A demethylases

N6-Methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m6A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m6A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Effect of lipoprotein / 中南大学学报(医学版)

OBJECTIVES@#To analyze the effect of hyperlipoproteinemia (α) on immediate expansion after coronary stent implantation guided by intravascular ultrasound (IVUS).@*METHODS@#A total of 160 patients (175 lesions) with coronary heart disease diagnosed by coronary artery angiography, who were performed percutaneous intervention guided by IVUS in the Department of Cardiology, Third Xiangya Hospital, Central South University, were enrolled retrospectively.According to the concentration of lipoproteina, the patients were divided into 2 groups: a hyperlipoproteinemia (α) group and a control group. Cardiac ejection fraction was measured with echocardiography. Logistic regression was used to analyze the influential factors for hyperlipoproteinemia (α). The target vessel was examined by IVUS to analyze the immediate expansion effect of hyperlipoproteinemia (α) after stent implantation.@*RESULTS@#The mean stent expansion index, lesion length, stent number, stent symmetry index and posterior balloon diameter were (94.73±18.9)%, (52.92±29.1) mm, (2.11±0.85), (83.62±13.07)%, and (9.46±2.00) mm in the hyperlipoproteinemia (α) group, respectively. Compared with the control group, there were significantly difference (all @*CONCLUSIONS@#Hyperlipoproteinemia (α) appears to be a predictor of stent underexpansion, and the decreased creatinine clearance rate is an independent risk factor for hyperlipoproteinemia (α).

The epigallocatechin gallate derivative Y reverses drug resistance mediated by the ABCB1 transporter both and

Previously, we reported that Y, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y in reversing drug resistance both and by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Establishment and characterization of arsenic trioxide resistant KB/ATO cells

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

The reversal of antineoplastic drug resistance in cancer cells by β-elemene / 癌症

Multidrug resistance (MDR), defined as the resistance of cancer cells to compounds with diverse structures and mechanisms of actions, significantly limits the efficacy of antitumor drugs. A major mechanism that mediates MDR in cancer is the overexpression of adenosine triphosphate (ATP)-binding cassette transporters. These transporters bind to their respective substrates and catalyze their efflux from cancer cells, thereby lowering the intracellular concentrations of the substrates and thus attenuating or even abolishing their efficacy. In addition, cancer cells can become resistant to drugs via mechanisms that attenuate apoptosis and cell cycle arrest such as alterations in the p53, check point kinase, nuclear factor kappa B, and the p38 mitogen-activated protein kinase pathway. In this review, we discuss the mechanisms by which β-elemene, a compound extracted from Rhizoma zedoariae that has clinical antitumor efficacy, overcomes drug resistance in cancer.

PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR

Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7(-/-) mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P-glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non-toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1 μmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.

Recent advances regarding the role of ABC subfamily C member 10 (ABCC10) in the efflux of antitumor drugs / 癌症

ABCC10, also known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily. ABCC10 mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs. The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane. ABCC10 is a broad-specificity transporter of xenobiotics, including antitumor drugs, such as taxanes, epothilone B, vinca alkaloids, and cytarabine, as well as modulators of the estrogen pathway, such as tamoxifen. In recent years, ABCC10 inhibitors, including cepharanthine, lapatinib, erlotinib, nilotinib, imatinib, sildenafil, and vardenafil, have been reported to overcome ABCC10-mediated MDR. This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy, particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.

Annona squamosa Linn: Cytotoxic activity found in leaf extract against human tumor cell lines

Cancer is a common cause of death in human populations. Surgery, chemotherapy and radiotherapy still remain the corner stone of treatment. However, herbal medicines are gaining popularity on account of their lesser harmful side effects on non-targeted human cells and biological environment. Annona squamosa Linn is a common delicious edible fruit and its leaf have been used for the treatment in various types of diseases

The objective of present study is to determine the anticancer potential of the organic and aqueous extracts of leaf of Annona squamosa L. MTT [3-[4, 5-dimethylthiazole-2yl]-2, 5-biphenyl tetrazolium bromide] assay against hepatocellular carcinoma cell line BEL-7404, lung cancer line H460, human epidermoid carcinoma cell line KB-3-1, prostatic cancer cell line DU145, breast carcinoma cell line MDA-MB-435, and colon cancer cell line HCT-116 Human primary embryonic kidney cell line HEK293 as control were used for the study

The crude extract [Zed] and Ethyl acetate extract [ZE] were found significant anticancer activity only on human epidermoid carcinoma cell line KB-3-1 and colon cancer cell line HCT-116

Antineoplastic activity of Holoptelea integrifolia [Roxb.] Planch bark extracts [in vitro]

Cancer remains the major public health concern with a number of cancer patients relying on chemotherapy as a treatment option. Although, advances in biomedical research have led to increased anticancer agents in recent years, the treatment is not always effective due to resistance, toxicity or other factors. Phytochemicals and their active components isolated from plants have provided diversified effective drugs many of them are currently used against cancer and other diseases. Holoptelea integrifolia [Roxb] Planch [Ulmaceae] is a widely distributed plant in many parts of the world, also grown in gardens of Pakistan. It is an ornamental plant with certain medicinal characteristics due to many valuable and active phyto constituents in various parts of the plant. We looked at in vitro antineoplastic effects of four different extracts, in butanol [BMBU], hexane [BMHx], ethyl acetate [BMET] and chloroform [BMCHF], from bark of Holoptelea integrifolia on small cell lung cancer, breast, prostate, coloretal and hepatocellular cancer cell lines. Plant extracts BMHx and BMET showed significant cytotoxic effects on breast and prostate cancer cells. These preliminary studies are encouraging to proceed further this research in future, regarding the isolation of active phytoconstituents in these extracts as well as its mechanism in chemoprevention and combination anticancer therapy

Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells / 癌症

Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia(ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance(MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line(K562-imatinib) through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein(P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine (6-MP) was decreased, whereas the ATP-dependent efflux of [14C]6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

Multidrug resistance associated proteins in multidrug resistance / 癌症

Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters. These ABC transporters together form the largest branch of proteins within the human body. The MRP family comprises of 13 members, of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell. They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH), glucuronate, or sulphate. In addition, MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH. Collectively, MRPs can transport drugs that differ structurally and mechanistically, including natural anticancer drugs, nucleoside analogs, antimetabolites, and tyrosine kinase inhibitors. Many of these MRPs transport physiologically important anions such as leukotriene C4, bilirubin glucuronide, and cyclic nucleotides. This review focuses mainly on the physiological functions, cellular resistance characteristics, and probable in vivo role of MRP1 to MRP9.

Role of ABC transporters in cancer chemotherapy / 癌症

Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.

The results and prognosis of different treatment modalities for solitary metastatic lung tumor from nasopharyngeal carcinoma: a retrospective study of 105 cases / 癌症

<p><b>BACKGROUND AND OBJECTIVE</b>Nasopharyngeal carcinoma (NPC) is known for its propensity for distant metastases. Lung metastasis is one of the most important causes of death for patients with NPC. Solitary metastatic lung tumor from NPC is a distinctive group associated with a better survival. This study was to find a more effective treatment modality and prognostic factors for the group.</p><p><b>METHODS</b>Clinical data of 105 cases of solitary metastatic lung tumor from NPC were retrospectively analyzed. Survival rate was calculated by the Kaplan-Meier method. The difference of survival between the patients treated by different modalities was evaluated by the log-rank test. The Cox univariate and multivariate analyses of gender, age, pathologic type, stage, adjuvant chemotherapy, evaluation of treatment for NPC, disease-free interval, size of metastatic tumor, pulmonary hilar and/or mediastinal lymph node metastasis, treatment modalities, recurrent distant metastases and/or relapse of NPC were conducted.</p><p><b>RESULTS</b>The local control rate was 53.8% in chemotherapy group, 88.0% in radiotherapy ± chemotherapy group, and 96.4% in operation ± chemotherapy group (P < 0.01). The most promising progression-free survival (PFS) and overall survival (OS) were obtained with operation ± chemotherapy and followed by radiotherapy ± chemotherapy. Both of them showed much better efficacy than chemotherapy (P < 0.001). The Cox multivariate analysis showed that recurrent distant metastases and/or relapse of NPC affected the survival (OR = 2.087, 95% CI = 1.277-3.410, P = 0.003). The T stage of NPC, size of metastatic tumor, hilar and/or mediastinal lymph node metastasis, and the treatment modality were independent prognostic factors.</p><p><b>CONCLUSIONS</b>Operation ± chemotherapy and radiotherapy ± chemotherapy are better treatment of solitary metastatic lung tumor from NPC, which could improve the local control and prolong the PFS and OS. Chemotherapy is recommended for patients with higher T stage of NPC, size of metastatic tumor ≥ 3 cm, pulmonary hilar and/or mediastinal lymph node metastasis.</p>

Survival analysis of 220 patients with completely resected stage-II non-small cell lung cancer / 癌症

<p><b>BACKGROUND AND OBJECTIVE</b>Surgery is the main therapy for patients with stage II non small cell lung cancer (NSCLC), but patients still have an unsatisfactory prognosis even though complete resection is usually possible. Adjuvant chemotherapy provides low rates of clinical benefit as well. We retrospectively analyzed prognostic factors of patients with completely resected stage II NSCLC to find patients with unfavorable factors for proper management.</p><p><b>METHODS</b>Clinical data of 220 patients with complete resections of stage II NSCLC at the Sun Yat sen University Cancer Center between January 1998 and December 2004 were retrospectively analyzed. Cumulative survival was analyzed by the Kaplan Meier method and compared by log rank test. Prognosis was analyzed by the Cox proportional hazards model.</p><p><b>RESULTS</b>The overall 3 and 5 year survival rates were 58.8% and 47.9%, respectively. The 3 and 5 year disease free survival rates were 45.8% and 37.0%, respectively. Of the 220 patients, 86 (39.1%) had recurrence or metastasis. A univariate analysis demonstrated that age (> 55 years), blood type, the presence of symptoms, chest pain, tumor volume (> 20 cm3), total number of removed lymph nodes (> or = 10), number of involved N1 lymph nodes (> or =3 ), total number of removed N2 lymph nodes (> 6), and the ratio of involved N1 lymph nodes (> or = 35%) were significant prognostic factors for 5 year survival. In the multivariate analysis, age (> 55 years), chest pain, tumor volume (> 20 cm3), total number of removed lymph nodes (> or = 10), and number of involved N1 lymph nodes (> or = 3) were independent prognostic factors for 5 year survival.</p><p><b>CONCLUSIONS</b>For patients with completely resectable stage II NSCLC, having > 55 years, presenting chest pain, tumor volumes > 20 cm3, and > or = 3 involved N1 lymph nodes were adverse prognostic factors, and > or = 10 removed lymph nodes was a favorable one. Patients with poor prognoses might be treated by individual adjuvant therapy for better survival.</p>

Prognostic effect of mediastinal lymph node dissection in patients with stage I non-small cell lung cancer / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the prognostic effect of mediastinal lymph node dissection in patients with stage I non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>The clinical data of 330 patients with stage I NSCLC who were treated with curative resection from January 1994 to December 2003 were reviewed retrospectively. According to the extent of mediastinal lymph node dissection and the pathology report, the patients were assigned to lung resection combined with mediastinal lymph node dissection (LND) group or with lymph node sampling (LNS) group. The Kaplan-Meier method was used for survival analysis. COX proportional hazards model was used for multivariate analysis.</p><p><b>RESULTS</b>There were 233 (70.6%) male patients and 97 (29.4%) female patients. The median age was 60 years old. Ninety-eight patients were in stage IA and 233 in stage IB. One hundred and forty patents were in group LND and 190 in group LNS. The mean number of removed lymph nodes in group LND and group LNS were (13.3 +/- 4.7) and (5.2 +/- 3.0) (P < 0.01), respectively. The mean of mediastinal lymph node station sampled in group LND and group LNS were (3.7 +/- 0.9) and (1.3 +/- 1.1) (P < 0.01), respectively. The 5-year and 10-year survival rates of patients in group LND were 72.0% and 66.1%, while in group LNS were 65.9% and 43.0% (P < 0.05), respectively. Other prognostic factors included symptom, staging, visceral pleura invasion and tumor size. LND was disclosed as a favourable prognostic factor at COX multivariate analysis, together with absence of symptom at diagnosis.</p><p><b>CONCLUSION</b>As compared with LNS, LND can improve survival in stage I NSCLC.</p>