The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment

A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.

PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells and o

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression

Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.

18F-FDG PET-CT in unknown-source of elevated serum carcinoembryonic antigen [CEA] level

Objective: to investigate the clinical value of 18F-FDG PET-CT in the diagnosis of malignant tumor when serum carcinoembryonic antigen [CEA] level is elevated for unknown primary lesion

Study Design: a descriptive study

Place and Duration of Study: department of Nuclear Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Henan, China, from March 2015 to March 2017

Methodology: a total of 120 cases of parallel 18F-FDG PET-CT examination with serum CEA level of patients with unexplained source examined were chosen. Those with a known disease or with incomplete record of clinical and/or relevant laboratory examinations were excluded. Pathological examination, results of clinical follow-up and other imaging tests constituted the clinical value of 18F-FDG PET-CT in the diagnosis of tumor. For patients who had underwent the determination of serum CEA more than twice, CEA doubling time [DT] was also calculated. The serum CEA level and CEA DT of benign versusmalignant 18F-FDG PET-CT imaging results were compared

Results: thirty [25.00%] cases were finally diagnosed as malignant tumors, and 90 [75.00%] cases were excluded labelled benign condition. There was one false positive case and one false negative case each with 18F-FDG PET-CT diagnosis. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 96.7%, 98.9%, 98.3%, 96.7% and 98.9%, respectively. The serum CEA level of patients with positive 18F-FDG PET-CT imaging was higher than that of 18F-FDG PET-CT negative patients [p<0.001]. The serum CEA DT of patients with positive 18F-FDG PET-CT imaging was shorter than that of 18F-FDG PET-CT negative patients [p<0.001]. The receiver operating characteristic [ROC] curve analysis showed that the diagnostic efficacy of 18F-FDG PET-CT was best at serum CEA of 14.31 micro g/L

Conclusion: 18F-FDG PET-CT imaging has high diagnostic value for patients with elevated serum CEA. For patients with serum CEA over 14.31 micro g/L, the diagnostic value of 18F-FDG PET-CT for malignant tumors is more reliable

Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 and

Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.

Targeting calcium signaling in cancer therapy

The intracellular calcium ions (Ca) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Cahomeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Casignaling for cancer therapy has become an emerging research area. This review summarizes some important Cachannels, transporters and Ca-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Cachannels/transporters or Ca-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Casignaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Cachannels or transporters.

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.

Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.

Mechanisms of resistance to EGFR tyrosine kinase inhibitors

Since the discovery that non-small cell lung cancer (NSCLC) is driven by epidermal growth factor receptor (EGFR) mutations, the EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g., gefitinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette (ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies.

Multidrug resistance-associated proteins and their roles in multidrug resistance / 药学学报

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. Multidrug resistance-associated proteins (MRPs) play an important role in the process of MDR. As an ATP-binding cassette (ABC) transporter superfamily, MRPs are selective and specific drug efflux pumps. In this paper, physiological characteristics, structural characteristics and resistance profile of MRPs and the associated reversal studies are reviewed.

Progress of Molecular Targeted Drug-Cetuximab(C225) / 生物化学与生物物理进展

The epidermal growth factor receptor (EGFR) provides a rational target for cancer therapy as it is commonly overexpressed in a variety of solid tumors, and its deregulation is correlated with resistance to chemotherapy and radiotherapy and a poor prognosis. Cetuximab (C255), a specific monoclonal antibody directed against EGFR, is synergistic with chemotherapy and radiotherapy and has been licensed for the treatment of irinotecan refractory colorectal cancer (CRC) and squamous cell cancer of the head and neck (SCCHN), which express EGFR. In addition, the clinical trials about cetuximab for the treatment of non-small cell lung cancer (NSCLC), breast and pancreas carcinoma are ongoing, and cetuximab has been proven to a novel strategy for the treatment of cancer with the overexpression of EGFR.

Progress of study on lapatinib / 中国药理学通报

EGFR/HER-2 is an attractive therapeutic target for solid tumors.Lapatinib is an orally administered dual inhibitor of EGFR/HER-2 tyosine kinases.Preclinical experiments in vitro and in vivo models indicate that lapatinib is active against various solid tumors.Phase Ⅰ trials have shown an acceptable adverse event.Phase Ⅱand Ⅲ trials demonstrate the promising results for the treatment of metastatic,refractory,inflammatory,or brain metastatic breast cancer.With the further developments of biology,the molecular targeted chemotherapy becomes a novel adjuvant therapy for advanced breast cancer patients.

Research advances in sorafenib:a multiple targeted anti-tumor agent / 中国药理学通报

Sorafenib,a novel oral multikinase inhibitor,targts on serine/threonine kinase and tyrosine kinases receptor of the tumor cells and vasculature.So Sorafenib can inhibit the tumor cell proliferation and revascularization.400 mg sorafenib administered twice a day is chosen as the recommended dosage for several phase Ⅰ studies,and it shows broad-spectrum antitumor activity in renal cancer,hepatocellular carcinoma,melanoma and non-small-cell lung cancer(NSCLC)in phase Ⅱ and Ⅲ clinical trials.Now FDA has approved the usage of sorafenib in renal cancer therapy.

Antitumoral effects of annonaceous acetogenins / 中国药理学通报

A large number of natural acetogenins have been isolated from se veral genera of the plant family Annonaceae. Many of these compounds have very p otent and diverse biological effects such as cytotoxic, antitumour, anti-malari al, pesticidal and anti-feedant activities. This paper reviews research finding s about the effects of annonaceous acetogenins on antitumor, MDR, mechanism of ac tion, structural-activity relationships etc.

Inhibitor of apoptosis proteins(IAP):Novel anticancer targets / 中国药理学通报

An endogenous suppressor of apoptosis, the inhibitor of apoptosis proteins(IAP) plays a key role in the occurrence and progression of cancer. In recent years cancer researches have been focused on gene-specific inhibitors with IAP as the target, so as to seek gene therapeutic strategies of less toxicity and higher efficiency. As members of IAP family, survivin and livin are over-expressed in tumors. Meanwhile, Smac can directly inhibit IAP. These findings suggest a promising alternative strategy for developing novel anticancer therapies.-

The development of the reversal of the tumor multidrug resistance / 中国药理学通报

Multidrug resistance(MDR)of tumor cells has become the main impediment that influence the curative effect of cancer chemotherapy. Although there are many mechanisms can generate the multidrug resistance, the overexpression of P-glycoprotein encoded by the multidrug resistance-1(mdr1) gene is the main cause in the formation of MDR. Seaching for innocuous and effective reversal of MDR is not only a method of improving the efficiency of cancer chemotherapy but also the problem desiderated to be resolved in chemotherapy domain.

Study of non-linearity relation of MTS cytotoxicity assay / 中国药理学通报

AIM We found in experiment that the relation of cell number-OD in MTS cytotoxicity assay is non-linearity. In this paper we probe into the relations of cell number-OD and drug dose-inhibition rate. METHODS Cells HL-60 and Raji were used in this experiment. Assay on the relation of cell number-OD: Cells of different concentrations were seeded into 96 well plates. OD was read at 490 nm after incubating with MTS for 1～5 hour. The regression curves were estimated from the data with the software SPSS 11.0. Cytotoxicity assay: Cells were seeded into 96 well plate and incubated with drug of different doses for 72 hours. OD was read at 490 nm after incubating with MTS for 3 hour. The regression curves were estimated from the data with the software SPSS 11.0. RESULTS The cubic curves fit well the relations of cell number-OD of the 2 strains of cells at 5 time points and the coefficient R2 of these cubic curves is 0.997～1.000, greater than the R2 0.938～0.993 of linear model. For the relations of dose-inhibition rate, the cubic curves also have best fitness and their R2 is 0.998～1.000 greater than the R2 0.948～0.987 of linear model of logarithm dose-probit. CONCLUSION For the relations of cell number-OD in MTS cytotoxicity assay, the fitness of cubic curves are better than the linear model. A more accurate IC 50 would be obtained by the cubic curve equation than by probit regression that is in common use.