Combination Of Adriamycin Research Articles

Abstract 2717: Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia

Abstract Various types of chemotherapeutic agents are widely used to treat a variety of human neoplasms. Nonetheless, its clinical use is hampered because of severe adverse side effects such as alopecia, neutropenia, pain, cachexia, conception impairment etc. Chemotherapy-induced alopecia (CIA) is one of the fundamental unsolved problems of clinical oncology that often encountered in cancer treatment. CIA has been reported to be caused by skin inflammation through oxidative stress, DNA damage, and inflammatory responses. However, the best remedy for CIA is still not established. In a new strategy, we show that WK0202 compound as a strong NQO1 substrate that modulates the intracellular NAD+ levels by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action and plays important role in hair regrowth response to single (cyclophosphamide-CYP) or combined (taxol, adriamycin and cyclophosphamide-TAC) cancer therapy. Particularly, we demonstrated that cellular NAD+ levels as well as SIRT1 activity and its expression was decreased in skin with hair follicles after CYP and TAC treatment, and PARP-1 hyperactivation was associated with CIA through increased nuclear factor (NF)-κB p65 and p53 acetylation in wild type, NQO1-/- and K14-/- C57BL/6 mice. However, an increase in NAD+ levels by WK0202 completely restored SIRT1 activity and its expression, and subsequently deacetylated NF-κB p65 and p53 in wild type, however not in NQO1-/- and K14-/- mice thereby attenuating CIA. Therefore, modulation of NAD+ levels by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated hair loss, including CIA. Citation Format: Dipendra Khadka, Gi-Su Oh, Hyung-Jin Kim, SeungHoon Lee, Su-bin Lee, Subham Sharma, Seon Young Kim, Tae Hwan Kwak, Sei-Hoon Yang, Hyuk Sim, Hong-Seob So. Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2717.

Alveolar soft PART sarcomas (ASPS): A tertiary care center experience from India.

e22553 Background: Alveolar soft part sarcomas (ASPS) are rare, vascular, soft tissue sarcomas and response to conventional chemotherapy is disappointing. There is sparse data from India and other lower and middle-income countries (LMICs) and merits exploration. Methods: This is a retrospective analysis of patients of ASPS treated at Tata Memorial Center, patterns of care and outcomes were analyzed. Results: Fifty four patients of ASPS were treated between January 2002 to July 2018. The median age was 30 years and most common primary site 45 (80%) was extremities. Distant metastasis were seen in 36 (67%) patients; 20 upfront and 16 on recurrence. In the period from 2002-2014, 18/34 (54%) patients were declared “best supportive care” for want of effective systemic therapies. Only 16 (47%) patients with metastatic disease received systemic chemotherapy. 8 (11%) patients received conventional chemotherapy. Most commonly used regimen was combination of Ifosfamide and Adriamycin, however, 5/8 ( 62.5%) had progressive disease on chemotherapy and 37.5% had grade ≥3 toxicity mainly in form of neutropenias . Since the year 2015, the pattern of care evolved and 6 patients with metastatic disease were treated with antiangiogenic therapies (Sunitinib and Pazopanib). Responses were seen in 4/6 (66.6%) including 2 partial and 2 complete responses. The median progression free survival of these patients was 23 months (95% CI 14.3- 27.3 months) and was significantly better than that of conventional therapies - 7 months (95% CI 5.1-9.8 months) p = 0.03. Conclusions: ASPS is a systemic disease with high metastatic potential and poor chemosensitivity. Our institute practice has evolved from a policy of therapeutic nihilism to that of effective and feasible treatment in form of antiangiogenic therapy with meaningful responses.

Combination of quercetin and Adriamycin effectively suppresses the growth of refractory acute leukemia.

The present study aimed to investigate the effect of combined treatment with quercetin and Adriamycin (doxorubicin) on the development of refractory acute leukemia. Primary leukemic cells were isolated from patients with refractory drug-resistant acute leukemia. The Cell Counting Kit-8 assay was used to detect the proliferation of cells treated with a range of doses of Adriamycin, quercetin and a combination of the two drugs. Non-irradiated mice were used to establish a T cell acute lymphoblastic leukemia (T-ALL) model, which was subsequently treated with Adriamycin, quercetin and a combination of the two drugs. The survival time was recorded, and white and red blood cells and platelets in mouse peripheral blood were counted. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of cardiac tissues were measured as indicators of oxidative stress and damage. Proliferation of primary leukemic cells was reduced by Adriamycin depending on the dose (0.06, 0.6 or 6 µg/ml) and treatment duration (24, 48 or 72 h) compared with the vehicle treated group. Co-treatment with quercetin achieved a similar suppression of leukemic cell proliferation when a lower dose of Adriamycin (0.03, 0.3 or 3 µg/ml) was administered for the same duration. The survival of non-irradiated mice with T-ALL was improved by co-treatment with a high dose of Adriamycin and quercetin compared with either treatment alone. Compared with treatment with Adriamycin alone, the combined treatment with Adriamycin and quercetin significantly enhanced the SOD activity and reduced the MDA content in the heart. Therefore, quercetin may enhance the effects of Adriamycin on refractory acute leukemia.

SM‑164 enhances the antitumor activity of adriamycin in human U2‑OS cells via downregulation of X‑linked inhibitor of apoptosis protein.

The antitumor effects of SM-164 and adriamycin (ADM) on human osteosarcoma U2-OS cells, the underlying mechanism are yet to be investigated. In the present study, U2-OS cells were divided into control, ADM, SM-164, and ADM + SM-164 groups. In addition, cells treated with both SM-164 and ADM were further divided into three subgroups: SM-164 + ADM, SM-164 + ADM + vector and SM-164 + ADM + X-linked inhibitor of apoptosis protein (XIAP) silencing groups. XIAP expression was achieved via transfection with shRNA lentiviral vectors. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression of caspases-7, −9, and −3, poly ADP-ribose polymerase (PARP), XIAP, cellular inhibitor of apoptosis protein-1 (cIAP-1) and survivin. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. Compared with the control group, cell viability decreased, while apoptosis was increased in the ADM and SM-164-treatment group. ADM and SM-164 treatment promoted the expression of caspases-7, −9 and −3, and PARP, but reduced the expression of XIAP, survivin and cIAP-1. Compared with ADM + SM-164 group, XIAP silencing with ADM + SM-164 treatment further reduced cell viability, promoted apoptosis, increased caspase-7, −9 and −3, and PARP expression; however the expression of survivin and cIAP-1 were reduced. Combined ADM and SM-164 treatment may be considered as potential therapeutic agent in the treatment of osteosarcoma, possibly via reductions XIAP expression.

Ginsenoside Rg1 Prevents Chemotherapy-Induced Cognitive Impairment: Associations with Microglia-Mediated Cytokines, Neuroinflammation, and Neuroplasticity.

Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10mg/kg daily) was given 1week prior to DAC regimen for 3weeks. An amount of 10mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC's neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.

Elucidating the beneficial effects of melphalan, adriamycin, and corticoids in combination with bortezomib against multiple myeloma in vitro.

Combining bortezomib with other anti-cancer drugs or glucocorticoids is more efficient in multiple myeloma than bortezomib alone. However, the molecular mechanism of this beneficial effect is largely unknown. To investigate the effects of these compounds on bortezomib's anti-proliferative potency and its intracellular accumulation and potency to inhibit the chymotrypsin-like proteasomal subunit, seven myeloma cell lines were investigated after exposure to bortezomib alone or either combined with adriamycin plus dexamethasone (PAD regimen) or melphalan plus prednisolone (VMP regimen), respectively. PAD or VMP combinations did not alter cellular bortezomib uptake. However, PAD and VMP regimens increased bortezomib's chymotrypsin-like subunit inhibitory potency. This likely originates from indirect proteasome modulation, because adriamycin, dexamethasone, melphalan, or prednisolone did not inhibit this subunit when used alone. Strikingly, the anti-proliferative potency of bortezomib was not enhanced but slightly lowered in some cell lines when used in combinations. Adriamycin, dexamethasone, melphalan, or prednisolone can enhance bortezomib's chymotrypsin-like subunit inhibitory potency, likely by mechanisms indirectly influencing proteasome functionality.

2-Bromopalmitate sensitizes osteosarcoma cells to adriamycin-induced apoptosis via the modulation of CHOP

Osteosarcoma is the most common primary malignant bone tumour, but the survival rate of patients has plateaued since the mid-1980s. Adriamycin is an integral component of the current first-line chemotherapies used for osteosarcoma, but dose-dependent severe side effects often limit its clinical application. Here, we propose a potential combination regimen in which adriamycin plus 2-bromopalmitate, a palmitoylation inhibitor, exhibited powerful therapeutic effects on osteosarcoma. First, 2-bromopalmitate strongly increased the proliferation inhibition of adriamycin in both human osteosarcoma cell lines and primary osteosarcoma cells. Adriamycin-induced apoptosis in osteosarcoma cells was enhanced when synergized with 2-bromopalmitate. Our study indicated that the reactive oxygen species scavenger NAC and GSH could largely reverse the apoptosis induced by adriamycin combined with 2-bromopalmitate, demonstrating that reactive oxygen species played an essential role in this combination therapy. Moreover, CHOP was remarkably elevated in the combination group, and silencing of CHOP almost completely blocked the apoptosis induced by the combination of 2-bromopalmitate and adriamycin. Taken together, our study provides a prospective therapeutic strategy to eliminate osteosarcoma, which is propitious to clinical combination therapy development.

Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation.

Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy-induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis-related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy.

4-Hydroxybenzoic acid (4-HBA) enhances the sensitivity of human breast cancer cells to adriamycin as a specific HDAC6 inhibitor by promoting HIPK2/p53 pathway

Breast cancer is reported a very complex disease along with heterogeneous morphological characteristics and unrelated clinical behavior, and is a leading cancer among female. Nevertheless, chemo-resistance is frequently observed. Adriamycin (ADM) is a always employed drug to treat clinical breast cancer. However, strong resistance to ADM limited its clinical efficacy. Deregulation of HDAC6 activity is linked to various diseases including cancer resulting in accumulating interest for developing HDAC6 inhibitors. In the present study, for the first time, we found that 4-Hydroxybenzoic acid (4-HBA), as histone deacetylase 6 (HDAC6) inhibitor, could successfully reverse ADM resistance in human breast cancer cells. 4-HBA significantly promoted the anticancer effect of ADM on apoptosis induction, as evidenced by the increased expressions of Caspase-3 and PARP cleavage, which was associated with the promotion p53 and homeodomain interacting protein kinase-2 (HIPK2) expressions in ADM-resistant breast cancer cells. Furthermore, the suppressive effect of ADM on drug-resistant breast cancer cells was accelerated by 4-HBA through increasing the number of cells distributed in G2/M phase of cell cycle arrest. Inhibiting HIPK2/p53 pathway could abolish 4-HBA/ADM co-treatment-induced apoptosis and G2/M cell cycle arrest. Importantly, HDAC6 expressions were also significantly down-regulated in ADM-resistance breast cancer cells co-treated with ADM and 4-HBA. Additionally, 4-HBA clearly potentiated the anticancer role of ADM in the MCF-7 breast cancer animal model with low toxicity. Therefore, 4-HBA could be applied as an effective HDAC6 inhibitor to reverse human breast cancer resistance. Herein, the 4-HBA and ADM combination might represent as a useful therapeutic strategy to prevent human breast cancer.

Drug-induced expression of EpCAM contributes to therapy resistance in esophageal adenocarcinoma

BackgroundWith a less than 5% overall survival rate, esophageal adenocarcinoma (EAC) is one of the leading causes of death in the United States. Epithelial cell adhesion molecule (EpCAM) is a cancer stem cell (CSC) marker that is expressed in various epithelial carcinomas, including EAC. Accumulating evidence indicates that CSC subpopulations can initiate cancer development and, in addition, drive metastasis, recurrence and drug resistance. It has also been reported that EpCAM up-regulation in EAC may lead to an aggressive behavior and, thus, an adverse clinical outcome. Here, we aimed to determine whether treatment with standard chemotherapeutic agents may induce EpCAM expression and, concomitantly, increases in malignant potential and drug resistance in EAC.MethodsEpCAM expression was assessed in 20 primary human EAC/adjacent normal tissues, as well as in a human EAC-derived cell line (OE-19), in a pre-malignant Barrett’s Esophagus cell line (Bar-T) and in a benign esophageal cell line (HET 1-A), using immunohistochemistry, Western blotting and qRT-PCR, respectively. Drug-induced resistance was investigated in OE-19-derived spheres treated with (a combination of) adriamycin, cisplatin and 5-fluorouracil (ACF) using survival, adhesion and flow cytometric assays, respectively, and compared to drug resistance induced by standard chemotherapeutic agents (CTA). Finally, ACF treatment-surviving cells were evaluated for their tumor forming capacities both in vitro and in vivo using spheroid formation and xenograft assays, respectively.ResultsHigh EpCAM expression was observed in esophageal cancer tissues and esophageal cancer-derived cell lines, but not in adjacent benign esophageal epithelia and benign esophageal cell lines (HET 1-A and Bar-T). The OE-19 cell spheres were drug resistant and EpCAM expression was significantly induced in the OE-19 cell spheres compared to the non-sphere OE-19 cells. When OE-19 cell spheres were challenged with ACF, the EpCAM mRNA and protein levels were further up-regulated up to 48 h, whereas a decreased EpCAM expression was observed at 72 h. EpCAM down-regulation by RNA interference increased the ACF efficacy to kill OE-19 cells. Increased EpCAM expression coincided with the CSC marker CD90 and was associated with an aggressive growth pattern of OE-19 cell spheres in vivo.ConclusionsFrom our data we conclude that an ACF-induced increase in EpCAM expression reflects the selection of a CSC subpopulation that underlies tumor development and drug resistance in EAC.

Chemotherapy-Induced Cognitive Impairment Is Associated with Cytokine Dysregulation and Disruptions in Neuroplasticity.

Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.

Germacrone reverses adriamycin resistance in human chronic myelogenous leukemia K562/ADM cells by suppressing MDR1 gene/P-glycoprotein expression

Multidrug resistance (MDR) usually causes chemotherapy failure of chronic myelogenous leukemia (CML). Germacrone is a terpenoid compound and has been reported to reverse MDR in breast cancer cells. However, the effect of germacrone on MDR in CML cells was unknown. The aim of the present study was to evaluate the effect of germacrone on MDR in adriamycin resistance of CML cells. Treatment with a combination of germacrone and adriamycin synergistically inhibited the viability and increased LDH release in K562/ADM cells. Adriamycin induced the apoptosis and caspase-3 activity of K562/ADM cells, and the germacrone treatment significantly enhanced the induction. Adriamycin treatment inhibited the expression of Bcl-2 and induced the expression of Bax, and germacrone enhanced the effect of adriamycin. Germacrone decreased adriamycin-induced expression of MDR1 mRNA and P-gp protein. Overexpression of P-glycoprotein (P-gp) reversed the effect of germacrone on adriamycin resistance in K562/ADM cells. In conclusion, germacrone reversed adriamycin resistance in human chronic myelogenous leukemia K562/ADM cells by suppressing MDR1 gene/P-gp expression. The results indicated that germacrone might be a new MDR reversal agent for CML chemotherapy.

Effects of the Combination of Gliotoxin and Adriamycin on the Adriamycin-Resistant Non-Small-Cell Lung Cancer A549 Cell Line.

Acquired drug resistance constitutes an enormous hurdle in cancer treatment, and the search for effective compounds against resistant cancer is still advancing. Marine organisms are a promising natural resource for the discovery and development of anticancer agents. In this study, we examined whether gliotoxin (GTX), a secondary metabolite isolated from marine-derived Aspergillus fumigatus, inhibits the growth of adriamycin (ADR)-resistant non-small-cell lung cancer (NSCLC) cell lines A549/ADR. We investigated the effects of GTX on A549/ADR cell viability with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the induction of apoptosis in A549/ADR cells treated with GTX via fluorescence-activated cell sorting analysis, Hoechst staining, annexin V/propidium iodide staining, tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, and western blotting. We found that GTX induced apoptosis in A549/ADR cells through the mitochondria-dependent pathway by disrupting mitochondrial membrane potential and activating p53, thereby increasing the expression levels of p21, p53 upregulated modulator of apoptosis (PUMA), Bax, cleaved poly (ADP-ribose) polymerase (PARP), and cleaved caspase-9. More importantly, we discovered that GTX works in conjunction with ADR to exert combinational effects on A549/ADR cells. In conclusion, our results suggest that GTX may have promising effects on ADR-resistant NSCLC cells by inducing mitochondria-dependent apoptosis and through the combined effects of sequential treatment with ADR.

Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor

Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus. Furthermore, TSN could significantly reduce ABCB1 expression. We then found that TSN was capable of suppressing adriamycin-induced Akt phosphorylation, probably due to downregulation of the PI3K catalytic subunits P110α and P110β, and inhibition of DNA-PKcs. Importantly, the inhibitory effect of TSN on PI3K P110α and P110β expression was specifically observed in breast cancer cells but not in normal human cells. Moreover, TSN significantly potentiated the anti-cancer effect of ADM in the 4T1 breast cancer model and its inhibition rate was nearly 90%. Thus, TSN could be used as a novel PI3K inhibitor to reverse breast cancer resistance. The combination of ADM and TSN may represent a useful strategy for human breast cancer therapy.

Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection

Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two-day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment. Water maze test and manganese-enhanced magnetic resonance imaging were used to evaluate animals' cognitive performance and brain neuronal activity, respectively. Blood and brain tissues were collected for measurement of cytokines, cytokine regulators, and biomarkers for neuroplasticity. DAC treatment produced a striking cognitive impairment. Cotreatment with 100 mg/kg resveratrol ameliorated DAC-induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with both doses of resveratrol displayed significantly lower levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but markedly higher levels of the anti-inflammatory cytokines IL-4 and IL-10 in several sera and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway peroxisome proliferator activated receptor (PPAR)-γ/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), amino acid neurotransmitter receptors, and calmodulin-dependent protein kinase II (CaMKII). These results demonstrate the efficacy of resveratrol in preventing chemobrain and its association with cytokine modulation and neuroprotection.

A review of epidemiology and management of multiple myeloma in a resource poor country

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of terminally differentiated B lymphocytes. Rational use of proteasome inhibitors, immunomodulators, anti CD38 or CD 138, and tandem autologous stem cell transplant have improved 5-year overall survival beyond 50% in advanced countries. However, the disease prevalence is probably highest in Sub-Saharan Africa where diagnostic and treatment facilities are lacking. The authors have reviewed published articles on epidemiology and outcomes of MM in Nigeria in the light of international recommendations with the aim of suggesting adaptable practices in a resource-poor environment. Publications from Nigeria were obtained from search engines such as Google Scholar and PubMed while recent guidelines were obtained from websites of the National Comprehensive Cancer Network and Medscape Oncology. The mean age at presentation ranged between 54 and 62 years, and there was a higher prevalence among males (ratio 1.1: 1–4.4: 1). A study in Nigeria found an increased incidence in oil-producing areas. In earlier publications between 2005 and 2007 years, about a quarter of patients could not afford treatment and most of the patients presented in advanced stages of the disease. During that period, the mean survival was 7 months and only 13.3% lived beyond 2 years. The treatment then was based on either melphalan ± prednisolone or combination of vincristine, adriamycin, and dexamethasone. By 2012/14, thalidomide, bortezomib, biphosphonates, radiotherapy, and renal dialysis were introduced with a mean survival of 4 years. Optimization of available facilities would, therefore, improve the disease-free survival.

Adriamycin in combination with dexamethasone and octreotide lacks activity on the treatment of a 4T1 metastatic breast cancer model.

The aim of this study was to evaluate whether the palliative treatment for metastatic disease with dexamethasone (DEX) plus octreotide (OCT) can improve the anticancer effects of the standard treatment with adriamycin (ADR) on a 4T1 metastatic breast cancer (MBC) model. 4T1 cells were first characterized for the expression of the somatostatin receptors 1-5 and were then inoculated onto the femur of BALB/C mice. Investigation protocols used 4T1 cell proliferation and invasion assays, analysis of radiographic images of the bone metastatic lesions, and overall survival of the diseased animals. The triple combination treatment regime (ADR+OCT+DEX) was ineffective for growth inhibition and showed an antagonistic effect on ADR activity in the 4T1 cell line in both proliferation and invasion assays. ADR treatment following the administration of the DEX+OCT regimen decreased the anticancer activity of ADR both on the grading of the bone metastatic lesions and on the overall survival of diseased animals. Moreover, the palliation treatment with OCT+DEX and in combination with ADR rather caused disease progression of the metastatic disease and bone lesions in a 4T1 MBC model in vivo. These results suggest that the administration of the DEX+OCT regimen, although may preserve palliative effects, neutralizes or reverses the anticancer effects of ADR on a 4T1 MBC model in vitro and in vivo. The simultaneous use of these drugs should be considered carefully in clinical practice.

Synergistic combination of YS-1 and adriamycin inhibits human renal cancer through ERK1/2 signaling pathway invitro and invivo.

Adriamycin (ADM) is a principal drug for the treatment of renal cell cancer (RCC). Due to its limited response and high renal and cardiac toxicity, synergistic effects of ADM in combination with other drugs have been widely researched. In this study, we found the combination between YS-1 and ADM, performed higher anticancer activity on 786-O human RCC cells invitro and invivo, than that reported on its anti-angiogenesis effect compared with monotherapy of ADM. Our data showed that when combined with ADM, YS-1 promoted the sensitivity of 786-O cells to ADM. The combination of YS-1 and ADM also inhibited cell proliferation, but without affecting cell apoptosis. We found that ADM monotherapy treatment notably upregulated the activity of extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2), but when combined with YS-1, the p-ERK1/2 level was reduced; then inhibited the Ras/Raf/MEK pathway. Additionally, the synergistic effects on cell cycle arrest inhibition were eliminated when ERK1/2 was silenced using siRNA. Our combination therapy of YS-1 with ADM showed the strongest antitumor effects invivo (inhibition ratio: 5mg/kg YS-1 combined with 1 mg/kg ADM, 68.19%) in comparison with individual effects (inhibition ratio: 5mg/kg YS-1, 30.07%; 1mg/kg ADM, 50.42%). Collectively, these findings indicated that YS-1 did not only enhance the ability of ADM to inhibit tumor proliferation, but also reduce the renal toxicity to protect the normal renal tissues.

ED15.02 Chemotherapy and Targeted Therapies of Thymic Malignancies

ED15.02 Chemotherapy and Targeted Therapies of Thymic Malignancies

Combination of temsirolimus and adriamycin exhibits an enhanced antitumor effect in hepatocellular carcinoma

The oncogenic PI3K/Akt/mTOR pathway is frequently activated in hepatocellular carcinoma (HCC). The aim of this study is to investigate the anti-HCC effect of combination of temsirolimus, an mTOR inhibitor, and adriamycin, a routinely used drug for treating HCC. Proliferation of HCC cells exposure to temsirolimus, adriamycin, and their combination was determined using MTT assay in vitro as well as in a nude mice model in vivo. Cell apoptosis was examined using flow cytometry. Expressions of apoptosis-related proteins including caspase-9, -3, PARP, Bax, and Bcl-2 were determined using Western blotting. Temsirolimus plus adriamycin showed an enhanced inhibitory effect on cell proliferation compared to temsirolimus or adriamycin in HCC cells PLC/PRF/5, BEL7402, and HuH7 in vitro. The drug combination solicited a higher percentage of apoptosis cells and induced higher levels of cleaved caspase-9, -3, and PARP than temsirolimus or adriamycin used alone. The ratio of Bax/Bcl-2 was increased in cells exposed to the combination treatment. The enhanced anti-tumor effect of this drug combination was verified in a nude mice model. We also observed that half doses of temsirolimus and adriamycin used in combination achieved a comparable tumor growth inhibitor rate with full dose of temsirolimus or adriamycin used alone. Temsirolimus plus adriamycin exhibited an enhanced antitumor effect in HCC and this drug combination might have a potential value in treatment of HCC. Studies are warranted to comprehensively evaluate the efficacy and safety of this regimen in the future.