Anticancer Drug Treatment Research Articles

Abstract 5664: PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model

Abstract Chemotherapy-induced neutropenia (CIN) is a common dose-limiting toxicity in cancer patients undergoing cytotoxic chemotherapy. It is generally understood that myelosuppression is the major mechanism resulting in CIN. However, an excessive extravasation (diapedesis) of neutrophils in response to tissue damage-caused by anti-cancer agents is also a possible mechanism. In this study, we have investigated the effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) for the maintenance of circulating neutrophil in the gemcitabine induced neutropenia. In CIN mouse model using anticancer drugs, PLAG effectively protected the loss of circulating neutrophils as similar to CXCR2 antagonist, reparixin. And succeeded in vitro neutrophil migration assay also revealed that chemo-attractive activity of neutrophil induced by treatment of anticancer drugs was completely interrupted by PLAG addition. Chemokine (C-X-C motif) ligand 2 (CXCL2) and CXCL8 were effectively induced by treatment of gemcitabine with dose dependent manner in monocyte cell lines and mainly mediated via the signal transducer and activator of transcription 3 (STAT3) signaling pathway. PLAG effectively attenuated gemcitabine induced CXCL2 and CXCL8 expression via interrupting STAT3 activity and also regulated gemcitabine induced macrophage 1 antigen (MAC-1) and L-selectin expression, which means that PLAG interrupted the acceleration of neutrophil extravasation under CIN. Also we have verified that PLAG analogues and metabolites were not affected on neutrophil migration unlike PLAG, suggesting that acetylated diacylglycerol has a key role to regulate on neutrophil migration. Collectively, modulating effect of PLAG on excessive neutrophil extravasation by chemotherapy via attenuating STAT3/CXCL2(8) pathway could be used as very powerful regimen for preventing of neutropenia during diverse chemotherapy. Citation Format: Yong-Jae Kim, Jinseon Jung, Ha-Reum Lee, Ki-Young Sohn, Heung-Jae Kim, Sun Young Yoon, Jae Wha Kim. PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5664. doi:10.1158/1538-7445.AM2017-5664

Abstract 4832: Establishment of lung cancer organoid lines as a new preclinical model for lung cancer

Abstract Human cancers are composed of genetically and phenotypically heterogeneous subpopulations organized into a hierarchy of tumor initiating stem cells and various differentiated tumor cell. Cancer organoids seem to be more suitable in vitro models for targeting tumor heterogeneity than cell lines. We established cancer organoid lines from lung cancer patient tissues, recapitulating histology of human cancers in three dimensional culture conditions. Thirteen organoid lines from various lung cancer subtypes including adenocarcinoma, squamous cell carcinoma and small cell carcinoma were compared with their original human tumors in histologic features and genetic profiles. In the IHC staining, it revealed that organoids of adenocarcinomas have typical glandulo-papillary structures or mucin-containing tumor cells. Organoids of squamous cell carcinomas showed keratinization and intercellular bridges. Organoids of small cell carcinoma displayed typical neuroendocrine morphology. Using NGS cancer panel sequencing, the organoid lines maintained genetic characteristics of the original human tumors in major driver genes including EGFR, TP53, and RB mutation. In xenograft experiments, the organoid lines revealed stronger tumorigenesity than direct graft of human tumor tissues. Cancer organoids showed resistance to various anticancer drug treatments. In conclusion, our lung cancer organoid lines are alternative cancer model for preclinical researches recapitulating genotypic and phenotypic heterogeneity of original human tumors. Note: This abstract was not presented at the meeting. Citation Format: Minsuh Kim, Sung-Min Chun, Hyemin Mun, Young-Ah Suh, Se jin Jang. Establishment of lung cancer organoid lines as a new preclinical model for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4832. doi:10.1158/1538-7445.AM2017-4832

Abstract 4304: Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis

Abstract Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis Moriizumi Hisashi, Takanori Nakamura and Mutsuhiro Takekawa Div. of Cell Signaling and Mol. Med., IMS, Tokyo Univ. The mitogen-activated protein (MAP) kinase pathway is an important system for cellular responses to extracellular stimuli. Each of the MAPK pathways is composed of MAPKKK, MAPKK and MAPK. In mammalian cells, at least three subfamilies of MAPKs, namely ERK, p38 and JNK, are present. The ERK pathway is activated in response to mitogenic stimuli and plays a key role in proliferation and differentiation. In contrast, the p38 and JNK pathways [collectively called stress-activated protein kinase (SAPK) pathways] regulate cellular stress responses such as apoptosis and cell cycle arrest. MKK4 is unique among the members of the mammalian SAPKK family (i.e., MKK3/4/6/7) in its ability to phosphorylate and activate both p38 and JNK. Interestingly, inactivating mutations of the MKK4 gene are frequently found in many types of cancer. Although MKK4 has been suggested as a tumor suppressor, the molecular mechanism by which MKK4 inhibits tumorigenesis remains unclear. Here we demonstrate that MKK4 can be phosphorylated at specific serine and/or threonine residues by downstream MAPKs(named the “feedback-phosphorylation”)and thereby regulates stress-induced apoptotic cell death. By generating antibodies specific to these phosphorylation sites, we found that under stress conditions both Thr and Ser residues of MKK4 were phosphorylated by JNK, while only the Ser residue was phosphorylated by ERK in response to mitogenic stimuli. In order to clarify physiological significance of the feedback-phosphorylation, we then generated a phosphorylation-deficient mutant of MKK4 (MKK4-AA) by substituting both Thr and Ser residues with Ala. Although the feedback-phosphorylation did not affect the enzymatic activity, stability and subcellular localization of MKK4, we found that cells expressing MKK4-AA mutant suppressed apoptosis induced by various stresses stimuli such as UV irradiation and anticancer drug treatment. These results suggest that feedback-phosphorylation of MKK4 regulates stress-induced apoptosis. Moreover, we are currently investigating the mechanism of how MKK4 affects apoptotic cell death in response to feedback-phosphorylation. Citation Format: Hisashi Moriizumi. Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4304. doi:10.1158/1538-7445.AM2017-4304

Model-based prediction of myelosuppression and recovery based on frequent neutrophil monitoring

PurposeTo investigate whether a more frequent monitoring of the absolute neutrophil counts (ANC) during myelosuppressive chemotherapy, together with model-based predictions, can improve therapy management, compared to the limited clinical monitoring typically applied today.MethodsDaily ANC in chemotherapy-treated cancer patients were simulated from a previously published population model describing docetaxel-induced myelosuppression. The simulated values were used to generate predictions of the individual ANC time-courses, given the myelosuppression model. The accuracy of the predicted ANC was evaluated under a range of conditions with reduced amount of ANC measurements.ResultsThe predictions were most accurate when more data were available for generating the predictions and when making short forecasts. The inaccuracy of ANC predictions was highest around nadir, although a high sensitivity (≥90%) was demonstrated to forecast Grade 4 neutropenia before it occurred. The time for a patient to recover to baseline could be well forecasted 6 days (±1 day) before the typical value occurred on day 17.ConclusionsDaily monitoring of the ANC, together with model-based predictions, could improve anticancer drug treatment by identifying patients at risk for severe neutropenia and predicting when the next cycle could be initiated.

Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling

Cancer stem cells (CSCs) are increasingly considered to be responsible for tumor initiation, metastasis and drug resistance. The drug resistance mechanisms activated in CSCs have not been thoroughly investigated. Although neuropeptides such as vasoactive intestinal peptide (VIP) can promote tumor growth and activate antiapoptotic signaling in differentiated cancer cells, it is not known whether they can activate antiapoptotic mechanisms in CSCs. The objectives of this study are to unravel the cytoprotective effects of neuropeptides and identify antiapoptotic mechanisms activated by neuropeptides in response to anticancer drug treatment in CSCs. We enriched and purified CSCs (CD44+/high/CD24−/low or CD133+ population) from breast and prostate cancer cell lines, and demonstrated their stemness phenotype. Of the several neuropeptides tested, only VIP could protect CSCs from drug-induced apoptosis. A functional correlation was found between drug-induced apoptosis and dephosphorylation of proapoptotic Bcl2 family protein BAD. Similarly, VIP-induced cytoprotection correlated with BAD phosphorylation at Ser112 in CSCs. Using pharmacological inhibitors and dominant-negative proteins, we showed that VIP-induced cytoprotection and BAD phosphorylation are mediated via both Ras/MAPK and PKA pathways in CSCs of prostate cancer LNCaP and C4-2 cells, but only PKA signaling was involved in CSCs of DUVIPR (DU145 prostate cancer cells ectopically expressing VIP receptor) and breast cancer MCF7 cells. As each of these pathways partially control BAD phosphorylation at Ser112, both have to be inhibited to block the cytoprotective effects of VIP. Furthermore, VIP is unable to protect CSCs that express phosphorylation-deficient mutant-BAD, suggesting that BAD phosphorylation is essential. Thus, antiapoptotic signaling by VIP could be one of the drug resistance mechanisms by which CSCs escape from anticancer therapies. Our findings suggest the potential usefulness of VIP receptor inhibition to eliminate CSCs, and that targeting BAD might be an attractive strategy for development of novel therapeutics.

Phospholipase C δ1 negatively regulates autophagy in colorectal cancer cells

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Kirsten rat sarcoma viral oncogene homolog (KRAS) is frequently mutated in CRC, and KRAS mutations promote cell motility, growth, and survival. We previously revealed that the expression of phospholipase C (PLC) δ1, one of the most basal PLCs, is down-regulated in colon adenocarcinoma, and that the KRAS signaling pathway suppresses PLCδ1 expression. Although recent studies revealed that KRAS mutations activate autophagy in cancer cells, a relation between PLCδ1 and autophagy remains unclear. Here, we found that PLCδ1 overexpression suppresses the formation of autophagosomes, which are key structures of autophagy, whereas endogenous PLCδ1 knockdown increases autophagosome formation in CRC cells. We also showed that PLCδ1 overexpression promotes cell death under nutrient deprivation. Furthermore, PLCδ1 overexpression suppresses the autophagy induced by the anti-cancer drug oxaliplatin and promotes cell death under oxaliplatin treatment. These data suggest that PLCδ1 negatively regulates autophagy, and PLCδ1 suppression contributes to the tolerance of CRC cells harboring KRAS mutations to nutrient deprivation and anti-cancer drug treatment.

Mitochondria-Targeting Polydopamine Nanoparticles To Deliver Doxorubicin for Overcoming Drug Resistance.

Mitochondria play a critical role in diverse cellular processes, such as energy production and apoptosis regulation. The mitochondria-targeted drug delivery is becoming a potential novel strategy for overcoming drug resistance in cancer therapy. Herein, we synthesize nature-inspired dopamine-derived polydopamine (PDA) nanoparticles. Using triphenylphosphonium (TPP) as the mitochondrial penetration molecule to improve the target efficiency, we synthesize poly(ethylene glycol) (PEG)-modified PDA (PDA-PEG) and TPP-functionalized PEG-modified PDA (PDA-PEG-TPP) nanoparticles. Then anticancer drug doxorubicin (DOX) was loaded on PDA-PEG and PDA-PEG-TPP (PDA-PEG-DOX and PDA-PEG-TPP-DOX) nanoparticles, which are apt to deliver DOX to cell nuclei and mitochondria, respectively. To mimic the repeated anticancer drug treatment in clinical cases, we repeatedly treated the MDA-MD-231 cancer cells for a long time using DOX-loaded nanoparticles and find that the mitochondria targeting PDA-PEG-TPP-DOX has higher potential to overcome the drug resistance than the regular delivery nanoparticles PDA-PEG-DOX. These results indicate the promising potential of applying PDA-PEG-TPP-DOX nanoparticles in mitochondria-targeted drug delivery to overcome the drug resistance in long-time anticancer chemotherapy.

Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells

Aging of cardiac stem/progenitor cells (CSCs) impairs heart regeneration and leads to unsatisfactory outcomes of cell-based therapies. As the precise mechanisms underlying CSC aging remain unclear, the use of therapeutic strategies for elderly patients with heart failure is severely delayed. In this study, we used human cardiosphere-derived cells (CDCs), a subtype of CSC found in the postnatal heart, to identify secreted factor(s) associated with CSC aging. Human CDCs were isolated from heart failure patients of various ages (2–83 years old). Gene expression of key soluble factors was compared between CDCs derived from young and elderly patients. Among these factors, SFRP1, a gene encoding a Wnt antagonist, was significantly up-regulated in CDCs from elderly patients (≥65 years old). sFRP1 levels was increased significantly also in CDCs, whose senescent phenotype was induced by anti-cancer drug treatment. These results suggest the participation of sFRP1 in CSC aging. We show that the administration of recombinant sFRP1 induced cellular senescence in CDCs derived from young patients, as indicated by increased levels of markers such as p16, and a senescence-associated secretory phenotype. In addition, co-administration of recombinant sFRP1 could abrogate the accelerated CDC proliferation induced by Wnt3A. Taken together, our results suggest that canonical Wnt signaling and its antagonist, sFRP1, regulate proliferation of human CSCs. Furthermore, excess sFRP1 in elderly patients causes CSC aging.

Effect of Combined Anticancer Drugs Treatment on Heterogeneous Brain Tumors

In this paper, we developed mathematical models to investigate the effects of concurrent application of radiotherapy and chemotherapy in a homogeneous and heterogeneous brain tumor. The objective of this research is to understand whether added chemotherapy, as an independent source to radiotherapy enhances the process of destroying tumor cells and also improve the radiation response. We have developed a finite element method to solve the pressure and convection diffusion equations to analyze the combined effects of both radiotherapy and chemotherapy and also to predict the effect of spatial distribution of base line vascular, tissue, and drugs transport parameters of uniform base line values. We calculated two dimensional spatial interstitial fluid flows, the interstitial fluid velocity, interstitial fluid pressure, and the drug concentration within a spherical tumor. The results are compared with published data. The sensitivity analysis is performed and indicates that the spatial distribution of base line simulation of vascular, tissue, and drugs transport parameters is considerable. The results suggest that chemotherapy improves the therapeutic efficacy of radiation in brain tumor, mostly when administered concurrently. More clinical studies and further model developments are required to validate this prediction.

MP48-12 EXTRAORDINARY ELEVATION OF SERPINB2 GENE AFTER ANTI-CANCER DRUG TREATMENT IN BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2017MP48-12 EXTRAORDINARY ELEVATION OF SERPINB2 GENE AFTER ANTI-CANCER DRUG TREATMENT IN BLADDER CANCER Miho Hiraki, Naoko Arichi, Hirofumi Kishi, Haruki Anjiki, Hiroaki Yasumoto, and Hiroaki Shiina Miho HirakiMiho Hiraki More articles by this author , Naoko ArichiNaoko Arichi More articles by this author , Hirofumi KishiHirofumi Kishi More articles by this author , Haruki AnjikiHaruki Anjiki More articles by this author , Hiroaki YasumotoHiroaki Yasumoto More articles by this author , and Hiroaki ShiinaHiroaki Shiina More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1493AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The second line chemotherapy against advanced bladder cancer has not been established. We hypothesize that highly activated genes after anti-cancer drug treatment is related to the key for predicting the anti-tumor effect. For this purpose, a comprehensive analysis using cDNA microarray was performed to identify the common target genes after treatment of chemotherapeutic agent. METHODS Bladder cancer cell lines of T24, RT4, UMUC3, and prostate cancer cell line of PC3 were used as control. Clinical samples from 26 cases with muscle invasive bladder cancer who underwent radical cystectomy were also used. Anti-cancer drugs used were docetaxel (DTX), gemcitabine (GEM) and Cis-platinum (CDDP). The cell viability was evaluated by an MTT assay. Gene expression profiles in T24 cells were identified using cDNA microarray, which showed significant difference before and after treamnent of 1.1mM docetaxel (DTX). Individual gene expression was validated by quantitative RT-PCR. Functional study of the candidate genes was performed using specific siRNA transfection. RESULTS We identified SERPINB2 gene with the GO term of “negative regulation of apoptosis” as extraordinarily activated gene after DTX treatment (Z score=7.509) . In T24 and UMUC3 cells, SERPINB2 expression was significantly increased in a stepwise manner of DTX concentration, while no significant elevation of SERPINB2 was found in RT4 cells (Table). Likewise, CDDP extraordinarily enhanced the SERPINB2 expression in T24 and UMUC3, but not in RT4. On other hand, GEM significantly accelerated the SERPINB2 expression in T24, while it did not in UMUC3 and RT4. UMUC3 cells, in which high SERPINB2 expression was found before treatment, showed significant reduction of cell viability after transfection of SERPINB2 siRNA, suggesting that SERPINB2 might function as oncogene. In addition, in PC3 where SERPINB2 was highly expressed before treatment, SERPINB2 knockdown by siRNA transfection showed significant reduction of cancer cell survival. In clinical samples, there was no significant difference in SERPINB2 expression between normal and cancer tissues. Interestingly, SERPINB2 expression was significantly higher in 4 cases who underwent both neoadjuvant chemotherapy (NAC) and cystectomy than in 22 cases who did cystectomy alone. CONCLUSIONS In certain bladder cancers, SERPINB2 might function as oncogene and is highly up-regulated. Activation of SERPINB2, which is frequently found after anti-cancer agent treatment, might provide the essential information regarding the chemotherapeutic strategy in bladder cancer. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e641 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Miho Hiraki More articles by this author Naoko Arichi More articles by this author Hirofumi Kishi More articles by this author Haruki Anjiki More articles by this author Hiroaki Yasumoto More articles by this author Hiroaki Shiina More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

2-Deoxy-D-glucose suppresses the migration and reverses the drug resistance of colon cancer cells through ADAM expression regulation.

Cancer cell resistance to chemotherapy is associated with a poor prognosis. The compound 2-deoxy-D-glucose (2-DG) enhances the effect of chemotherapy against cancer cells lines in vitro and in vivo. However, its effect on the epithelial to mesenchymal transition (EMT) in drug-resistant cancer cells has not been fully elucidated. In this study, we investigated whether treatment of 5-fluorouracil or oxaliplatin-resistant colorectal cancer (CRC) cells with 2-DG suppressed their migratory activity and enhanced their susceptibility to chemotherapy. Chemoresistant CRC cells stably expressed drug resistance-related proteins (MDR1, MRP1, MRP2, and MRP3) and showed mesenchymal characteristics and a migratory phenotype. 2-DG treatment attenuated glycolysis-related enzyme expression, invasion activity, and EMT-related cytokine secretion in drug-resistant CRC cells. In addition, 2-DG inhibited the activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17. Gene silencing of ADAM10 and ADAM17 with small interfering RNA downregulated mesenchymal properties, reduced EMT-associated cytokine secretion, and rendered chemoresistant cells susceptible to anticancer drug treatment. Collectively, these findings suggest that increased glycolytic metabolism in drug-resistant cells has an effect on both migratory activity and cell viability through the activation of ADAM10 and ADAM17.

Vincristine-induced peripheral neuropathic pain and expression of transient receptor potential vanilloid 1 in rat

The clinical anti-cancer efficacy of vincristine is limited by the development of dose-dependent peripheral neuropathy. Up-regulation of transient receptor potential vanilloid 1 (TRPV1) is correlated with peripheral neuropathy following anti-cancer drug treatment. To analyze the contribution of TRPV1 to the development of vincristine-induced mechanical allodynia/hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after vincristine treatment. Mechanical allodynia/hyperalgesia was tested with von Frey filaments 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in rats. TRPV1 expression in DRGs following vincristine treatment was assessed with western blot analysis and in situ hybridization histochemistry. Vincristine-induced mechanical allodynia/hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Vincristine treatment increased the expression of TRPV1 protein in DRG neurons. In situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small in size. Immunohistochemistry showed that isolectin B4-positive small DRG neurons co-expressed TRPV1 protein 14 days after treatment. These results suggest that vincristine treatment increases TRPV1 expression in small DRG neurons. TRPV1 expression may contribute to the development of vincristine-induced painful peripheral neuropathy.

Quantifying episode-based costs of care under the oncology care model: Analysis of Medicare beneficiaries in the UAB cancer community network.

19 Background: The Oncology Care Model (OCM) is a specialty care model developed by the Centers for Medicare & Medicaid (CMS) Innovation Center aimed at providing higher quality, more highly coordinated cancer care and reducing costs for patients undergoing chemotherapy. The OCM calculates costs of care in a novel way by anchoring costs within episodes of care, defined as six-month intervals triggered by initial anti-cancer treatment, as opposed to diagnosis date. The purpose of this study is to assess costs within the OCM episodes of care. Methods: This was a secondary analysis of Medicare administrative claims data for beneficiaries 65 and older with cancer who received anti-cancer drug treatment (chemotherapy, hormone therapy) between 2012-2015 at an institution in the UAB Cancer Community Network (CCN). Total and service-specific costs (Medicare reimbursement to providers) per patient-episode were summed from inpatient, outpatient, chemotherapy, radiation therapy, testing/pathology, evaluation and management (E/M), home health, skilled nursing facility (SNF), and hospice claims. Prescription drug costs were not included. Mean costs for the first three OCM episodes were calculated and compared to (1) diagnosis-based costs (six-month intervals starting at cancer diagnosis) and (2) service type. Results: Average total cost in the first three OCM episodes of care was $24,922 (n=13,902), $18,534 (n=6,618), and $16,548 (n=4,672). Compared to episode-based cost, average total diagnosis-based cost was higher in the first episode of care ($33,244, n=9,615), and lower in the second and third episodes ($17,143, n=9,110; $12,897, n=8,002). Episode-based outpatient, inpatient, and chemotherapy costs were the highest service-specific costs in all three episodes of care (1st: $8,374, $5,493, $2,445; 2nd: $6,188, $3,913, $3,158; 3rd: $5,909, $3,251, $3,399). Conclusions: Costly chemotherapy and inpatient and outpatient visits indicate an opportunity for targeted improvement resulting in higher value care. Knowledge of current costs of care will aid oncology practices in transition to the OCM and in usage of value-based services for better quality cancer care.

Ultrasound contrast-enhanced study as an imaging biomarker for anti-cancer drug treatment: preliminary study with paclitaxel in a xenograft mouse tumor model (secondary publication)

PurposeThe purpose of this study was to assess tumor angiogenesis using contrast-enhanced ultrasonography (CEUS) of human prostate cancer cells (PC3) that were implanted in mice before and after paclitaxel injection.MethodsTwelve mice were injected with human PC3. The mice were grouped into two groups; one was the paclitaxel-treated group (n=6) and the other was the control group (n=6). Before administering paclitaxel into the peritoneal cavity, baseline CEUS was performed after the administration of 500 μL (1×108 microbubbles) of contrast agent. The area under the curve (AUC) up to 50 seconds after injection was derived from the time-intensity curves. After injection of paclitaxel or saline, CEUS studies were performed at the 1-week follow-up. Changes in tumor volume and the AUC in both two groups were evaluated. After CEUS, the microvessel density (MVD) was compared between the groups.ResultsIn the paclitaxel-treated group, the AUC from CEUS showed a significant decrease 1-week after paclitaxel administration (P=0.030), even though the tumor volume showed no significant changes (P=0.116). In the control group, there was no significant decrease of the AUC (P=0.173). Pathologically, there was a significant difference in MVD between both groups (P=0.002).ConclusionThe AUC from the time intensity curve derived from CEUS showed an early change in response to the anti-cancer drug treatment that preceded the change in tumor size. The findings of CEUS could serve as an imaging biomarker for assessing tumor responses to anti-cancer drug treatment.

A CLINICAL STUDY TO EVALUATE THE EFFICACY OF KASHMARYADI OIL (TRADITIONAL FORMULA) IN THE MANAGEMENT OF KHALITYA

Hair loss is a dermatological disorder that has been recognized for more than 2000 years. It is common throughout the world and has been estimated to affect nearly 2% of the world's population. Apart from metabolic and hereditary causes, alopecia has been observed as a major side effect of anticancer, immunosuppressant and many others drug treatments. To solve the above query and to find out a promising remedy, the present study has been undertaken. 
 In Ayurvedic approach, loss of hair is coined out as in term of Khalitya under the broad heading of Shiroroga. For this Moordha Taila (Shiroabyanga) is the management and when is done with Taila which is medicated by hair growing drugs is more efficacious. So in present study Kashmaryadi oil advocated in traditional medicine that has Keshya properties has been selected.
 Sixty patients were selected; they were examined and recorded their history in the performa that prepared including all the necessary aspects of Ayurveda and modern medical science. The patients were advised to give gentle massage to the scalp covering whole area with hair oil at night and rinse it in the morning.
 The clinical condition was assessed before, after two weeks, after four weeks and after follow up period. Using grading system assessed signs and symptoms. Hair fall, Darunaka, Kandu, Kesha Rukshatwa, Kesha Katinya, Kesha Tanutwa, Kesha Bhoomi Daha, Kesha Bhoomi Durganda were assessed and observed the significant reduction of symptoms. Considering the total treatment assessment there were 41.67% complete remission, 30% marked improvement, 16.67% moderate improvement, 8.33% mild improvement and 3.33% unchanged. No adverse reaction reported in this study period.
 It is concluded that Kashmaryadi oil is very effective in the treatment of hair loss.

An Improved Machine Learning Approach to Enhance the Predictive Accuracy for Screening Potential Active USP1/UAF1 Inhibitors

DNA repair mechanism is an important mechanism employed by the cancerous cell to survive the DNA damages induced during uncontrolled proliferation of cell and anti-cancer drug treatments. In this context, the Ubiquitin-Specific Proteases (USP1) in complex with Ubiquitin Associated Factor 1(UAF1) plays a key role in the survival of cancerous cell by DNA repair mechanism. Thus, this put forth USP1/UAF1 complex as a striking anti-cancer target for screening of anti-cancer molecule. The current research is aimed to improve the classification accuracy of the existing bioactivity predictive chemoinformatics model for screening potential active USP1/UAF1 inhibitors from high-throughput screening data. The current study employed feature selection method to extract key molecular descriptors from the publicly available high-throughput screening dataset of small molecules that were used to screen active USP1/UAF1 complex inhibitors. This study proposes an improved predictive machine learning approach using the feature selection technique and two class Linear Discriminant Technique (LDA) algorithm to accurately predict the active novel USP1/UAF1 inhibitor compounds.

ANTITUMOR EFFECT OF SUNITINIB AND BORTEZOMIB ON BREAST CANCER CELL LINE IN VITRO

The discovery for effective combinations of anticancer drugs for treatment for breast cancer is the actual problem in the experimental chemotherapy. In this paper we conducted a study of antitumor effect of the combination of sunitinib and bortezomib against MDA-MB-231 and SKBR-3 breast cancer cell lines in vitro. We found that bortezomib in non-toxic concentrations can potentiate the antitumor activity of sunitinib. MDA-MB-231 cell line has showed great sensitivity to the combination of bortezomib and sunitinib in vitro. Bortezomib and sunitinib caused reduced expression of receptor tyrosine kinases VEGFR1, VEGFR2, PDGFRa, PDGFRß and c-Kit on HER2- and HER2+ breast cancer cell lines

Inhibitory Effect of D-chiro-inositol on Both Growth and Recurrence of Breast Tumor from MDA-MB-231 Cancer Cells

D-chiro-inositol (DCI) is a secondary messenger in insulin signal transduction. It is produced in vivo from myo-inositol via action of epimerase. In this study, we evaluated antitumor activity of DCI against human breast cancer both in vitro and in vivo. In order to determine the inhibitory effects of DCI on growth of human breast cancer cells (MDA-MB-231), two different assessment methods were implemented: MTT assay and mouse xenograft assay. MTT assay demonstrated downturn in cell proliferation by DCI treatment (1, 5, 10, 20 and 40 mM) groups by 18.3% (p < 0.05), 17.2% (p < 0.05), 17.5% (p < 0.05), 18.4% (p < 0.05), and 24.9% (p < 0.01), respectively. Also, inhibition of tumor growth was investigated in mouse xenograft model. DCI was administered orally at the dose of 500 mg/kg and 1000 mg/kg body weight to treat nude mouse for 45 consecutive days. On the 45th day, tumor growth of DCI (500 mg/kg and 1000 mg/kg) groups was suppressed by 22.1% and 67.6% as mean tumor volumes were 9313.8 ± 474.1 ㎣ and 3879.1 ± 1044.1 ㎣, respectively. Furthermore, breast cancer stem cell (CSC) phenotype (CD44+/CD24-) was measured using flow cytometry. On the 46th day, CSC ratios of DCI (500 mg/kg) and co-treatment with doxorubicin (4 mg/kg) and DCI (500 mg/kg) group decreased by 24.7% and 53.9% (p < 0.01), respectively. Finally, from tumor recurrence assay, delay of 5 days in the cotreatment group compared to doxorubicin (4 mg/kg) alone group was observed. Based on these findings, we propose that DCI holds potential as an anti-cancer drug for treatment of breast cancer.

Strategic Perspectives on Improved Anti-Tumor Drug Effects in Combination with Clinically Equivalent or Lower Concentrations of Epigenetic Modifiers, DNA Methyltransferase Inhibitors, and Histone Deacetylase Inhibitors

The aim of this research is to facilitate the pursuit of improved chemotherapeutic drugs in combination with epigenetic modifiers. Both in vitro studies and a clinical study have described the combinations of DNA methyltransferase inhibitors with irinotecan and histone deacetylase inhibitors with 5-fluorouracil or gemcitabine to enhance their anti-cancer activities. The molecular mechanisms involved in the potentiation of anti-tumor activities were apoptosis regulation, cellular metabolism, DNA topoisomerase-I upregulation, cell-cell adhesion, regulation of transcription (DNA-templated), DNA repair, and the PI3K/AKT signaling pathway. More importantly, the priming effects and long-lasting effects induced by DNA methyltransferase inhibitors, when applied as a pretreatment, sensitized cancer cells to subsequent anti-cancer drug treatments. The combinations of 5-fluorouracil and gemcitabine with histone deacetylase inhibitors (depsipeptide and valproic acid, respectively), increased the expression of major histocompatibility complex class II, which may warrant further investigation for possible accurate biomarkers and therapeutic targets. As valproic acid downregulated histone deacetylase in patients recruited in a clinical phase I/II study, the activity of valproic acid may be associated with the enhanced anti-tumor activity in combination with 5-fluorouracil. This research provides a positive perspective on the combination therapy of anticancer drugs with epigenetic modifiers.

Raman endoscopy for monitoring the anticancer drug treatment of colorectal tumors in live mice.

A miniaturized Raman endoscope (mRE) system was employed to study the effects of anticancer treatment on colorectal tumors in a live murine model. The endoscope is narrow enough to observe the inside of the mouse colon under anesthesia. It has a channel for a ball lens mounted on a hollow fiber Raman probe (BHRP) to measure any targeted point under the visual control of the endoscope. Colorectal cancer tissue was observed to study the alterations of the tissue in response to anticancer drug treatment. Three anticancer drugs, 5-fluorouracil (5-FU), cisplatin (CDDP), and docetaxel, were employed. Although no alteration was recognized in the endoscopic visual observations at 2 weeks after the drug treatment, the Raman spectra obtained in the live mouse colon indicated that molecular changes of lipids and proteins were observed. This study demonstrates that in situ Raman analysis is highly sensitive for detecting the effects of anticancer drugs.