Radiosensitizing Activity Research Articles

Cytotoxicity and Radiosensitizing Activity of the Fatty Acid Synthase Inhibitor C75 Is Enhanced by Blocking Fatty Acid Uptake in Prostate Cancer Cells

Prostate cancers, like many other types of cancer, express elevated levels of fatty acid synthase (FASN) to make more fatty acids, which are required for energy, signaling, and proliferation. Because inhibition of FASN has been shown to sensitize tumors to chemotherapy and radiation, we studied the effect of C75, a radiosensitizing FASN inhibitor, and compared its single agent and radiosensitizing activities in 2 prostate cancer cell lines, PC3 and LNCaP, with alternative FASN inhibitors that have progressed into clinical trials. We also investigated the effect of serum and fatty acid supplementation on responses to FASN inhibitors, probing expression of key proteins related to fatty acid uptake in response to FASN inhibition, irradiation, and serum lipid concentration and how this may be modulated to increase the potency of C75. We demonstrated that C75 was the only FASN inhibitor to sensitize cells to ionizing radiation; no sensitization was apparent with FASN inhibitors TVB-3166 or Orlistat. The prostate cancer cell lines were able to take up fatty acids from the culture medium, and the availability of fatty acids affected sensitivity of these cells to C75 but not the other FASN inhibitors tested. C75 also increased expression of fatty acid transporter proteins FATP1 and CD36. Furthermore, blocking CD36 with antibody increased the sensitivity of cells to C75. We suggest that the potency of C75 is affected by fatty acid availability and that the effectiveness of FASN inhibitors in combination with ionizing radiation can be further enhanced by regulating fatty acid uptake.

Emerging strategies to target cancer metabolism and improve radiation therapy outcomes.

Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental stresses like hypoxia and nutrient deprivation. Radiation is extensively applied in a large number of cancer treatment protocols but despite its curative potential, radiation resistance and treatment failures pose a serious problem. Metabolic control of DNA integrity and genomic stability can occur through multiple processes, encompassing cell cycle regulation, nucleotide synthesis, epigenetic regulation of gene activity, and antioxidant defenses. Given the important role of metabolic pathways in oxidative damage responses, it is necessary to assess the potential for tumor-specific radiosensitization by novel metabolism-targeted therapies. Additionally, there are opportunities to identify molecular and functional biomarkers of vulnerabilities to combination treatments, which could then inform clinical decisions. Here, we present a curated list of metabolic pathways in the context of ionizing radiation responses. Glutamine metabolism influences DNA damage responses by mechanisms such as synthesis of nucleotides for DNA repair or of glutathione for ROS detoxification. Repurposed oxygen consumption inhibitors have shown promising radiosensitizing activity against murine model tumors and are now in clinical trials. Production of 2-hydroxy glutarate by isocitrate dehydrogenase1/2 neomorphic oncogenic mutants interferes with the function of α-ketoglutarate-dependent enzymes and modulates Ataxia Telangiectasia Mutated (ATM) signaling and glutathione pools. Radiation-induced oxidative damage to membrane phospholipids promotes ferroptotic cell loss and cooperates with immunotherapies to improve tumor control. In summary, there are opportunities to enhance the efficacy of radiotherapy by exploiting cell-inherent vulnerabilities and dynamic microenvironmental components of the tumor.

Enzymatic transformation and anti-tumor activity of Sargassum horneri fucoidan

Structure of the fucoidan from Sargassum horneri and products of its enzymatic transformation with molecular weight over 20 kDa were investigated. Fucoidan was hydrolyzed by recombinant fucoidanase FFA1 and its fraction of higher molecular weight was fractionated using anion-exchange chromatography, resulting in three sulphated polysaccharides of various molecular weight (63−138 kDa). Their structures were analyzed using NMR spectroscopy, showing the fucoidan (ShF) to be a branched polysaccharide with the backbone consisting of the repeating →3-α-l-Fucp(2SO3−)-1→4-α-l-Fucp(2,3SO3−)-1→ fragment and side chains including the α-l-Fucp-1→2-α-l-Fucp-1→ or α-l-Fucp-1→3-α-l-Fucp(4SO3−)-1→ fragments attached to the main chain at C4. The fragment F3 differing by molecular weight and side chain from other fucoidans fragments possessed the most significant anticancer and radiosensitizing activities.

Iodoquinazolinones bearing benzenesulfonamide as human carbonic anhydrase I, II, IX and XII inhibitors: Synthesis, biological evaluation and radiosensitizing activity

In the present work, we report the design and synthesis of a set of iodinated quinazolinones carrying benzenesulfonamide moiety as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The target compounds showed promising inhibitory activity against the four examined human (h) CA isoforms; I, II, IX and XII. Compounds 4-18 displayed variable inhibition constants, ranging as follows: 7.6–782.8 nM for hCA I, 34.4–412.1 nM for hCA II, 29.1–2225.3 nM for hCA IX and 8.8–429.4 nM for hCA XII. Compound 9, the most potent against the tumor-specific CA IX/CA XII (KI = 29.1 and 8.8 nM) gives the possibility to evaluate its cytotoxicity and selectivity in vitro against HepG-2, HCT-116 and MCF-7 cancer cell lines. Compound 9 showed significant cytotoxicity against the tumor cell lines (IC50 = 1.78, 1.94 and 3.07 μM, respectively) and relatively lower toxicity against WI38 normal cell line. The radiosensitizing activity of compound 9 was evaluated and displayed an increase in the radiation-induced cell death in cancer cells after receiving a single dose of 8 Gy gamma radiation. Thus, radiation was able to enhance the antiproliferative activity of compound 9. Molecular docking of 9 into the active site of CA IX and XII revealed the key interactions that could explain its potent activity and selectivity towards these isoforms.

N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression.

Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N6-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of γ-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.

Investigation of Mechanism Activity of Antitumor and Radiosensitizing Activity of Preparations К-26 and K-26w

Introduction. Tropolone alkaloid – colchicine, there is very interesting object for synthesis of its derivatives, with such properties as, alkylation, a low toxicity, high antineoplastic activity and especially overcoming of multidrug resistance (MDR). We had been developed the antineoplastic preparation К-26 derivative of colchicine. К-26 has shown high cytotoxic activity on 60 lines of tumoral cells of the human in vitro, at National Institute of the Cancer of the USA (NCI). Further on the basis of К-26 its water-soluble form named term К-26w has been received. The work purpose. Studying of the mechanism of action of preparations К-26 and К-26w on: alkylating ability, mitotic activity, topoisomerase II, MDR2, р53 and colony-forming cells spleen (CFCs). Materials and methods. All researches have been carrying out by a standard technique. Studying mitotic activity of preparations was carrying out on duodenum and tumor СаРа after preparation influence. On models of a tumor of the Sarcoma 180 action of preparations has been investigated: the alkylating - on synthesis DNA/RNA, nucleosoma DNA degradation, activity topoisomerase II; on an expression MDR2 and р53 genes. Studying CFCs carry out by a standard technique on outbred mice. Results. К-26, К-26w and etoposide inhibited in cells of the Sarcoma 180: synthesis DNA/RNA on 84/65%, 95/85% and 55/35%, accordingly, in relation to the control; activity topoisomerase II on 80%, 90% and 60% accordingly. By method RT-PCR it is shown, К-26, К-26w and etoposide: inhibited an expression of MDR2 gene on 83%, 91% and 62%; increase expression р53 gene to 74%, 88% and 55%, accordingly, under the relation of the control of referential gene GARDH (100%). High ability К-26 and К-26w in an induction apoptosis tumoral cells and CFCs to 12 units is shown. Conclusion. Revealed ability К-26 and К-26w to suppress synthesis DNA/RNA activity topoisomerases, to stimulate р53, and also to suppress an expression of a multidrug resistance MDR2 gene, it explains their high antineoplastic activity which is connected with mitotic activity leading to cell fission synchronization, and radiosensitization activity. Special interest represents found at К-26w and К-26 suppression MDR2 as they are aimed for treatment of such resistant tumor as a kidney cancer. Stimulation CFCs which provides formation of haemopoetic and immune cells can protect an organism from their intensive cytotoxic action.

Biosynthesis of Silver Nanoparticles Using Thymoquinone and Evaluation of Their Radio-Sensitizing Activity

Delivering an optimum radiation dose to the target and preserving the surrounding normal tissues are the main tasks in radiation therapy. Latterly, there is a special interest in formulations of metallic-based nanoparticles to be used as radio-sensitizers. One of these silver nanoparticles (AgNPs) have been used for a wide range of biomedical applications depending on their surface modifications, size, and shape. This study aims to fabricate and characterize green synthesized silver nano-formulations using thymoquinone (TQ), as reducing and capping agent and assessment of their radio-sensitizing effect against the highly aggressive MDA-MB-231 mammary adenocarcinoma. AgNPs were prepared with different sizes by changing the amounts of added TQ. The prepared silver nano-formulations have been characterized using different physical techniques. The radio-sensitization efficacy of prepared AgNPs has been assessed using MTT cytotoxicity assay. Further assessment, neutral comet assay, was carried out to investigate the amount of DNA double-strand breaks which occurred due to AgNPs radio-sensitization. TEM micrograph revealed that as the amount of the added TQ increased from 10, 20, and 40 mg, the average size of prepared silver nanoparticles (AgNPs-20, AgNPs-15, and AgNPs-10) was gradually decreased to be 20 ± 1.5 nm, 15 ± 2 nm, and 10 ± 1.8 nm, respectively. This was confirmed by DLS measurements and UV-Vis spectroscopy. Comet and MTT assay results showed that AgNPs have a size and concentration-dependent radio-sensitization activity, whereas the radiation dose enhancement for small-sized nanoparticles (AgNPs-10) was greater than that of larger sized (AgNPs-20 and AgNPs-15). Therefore, thymoquinone capping silver nanoparticles represent a promising engineered nano-formulation for enhancing cancer radiosensitivity.

Mesothelioma Cells Depend on the Antiapoptotic Protein Bcl-xL for Survival and Are Sensitized to Ionizing Radiation by BH3-Mimetics

The incidence of mesothelioma continues to rise and prognosis remains dismal owing to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of antiapoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of antiapoptotic proteins in the radioresistance of mesothelioma, identifying clinically relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiation therapy in preclinical models. Mesothelioma cell lines 211H, H2052, and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC50, 0.13-1.42 μmol/L) and radiosensitizing activities (sensitizer enhancement ratios, 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a 3-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells. Mesothelioma cells exhibit addiction to the antiapoptotic protein Bcl-xL, and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target.

Investigating the effect of radiosensitizer for Ursolic Acid and Kamolonol Acetate ‌ on HCT-116 cell line

PurposeThe aim of this study was evaluating the cytotoxic and radiosensitizing effects of Ursolic Acid (UA) and Kamolonol Acetate (KA) on HCT116 cell line and finally investigating the functional role of NF-κB and CCND1 genes in the radiosensitizing activity of UA and KA. Materials and methodThe cytotoxic effects of UA and KA by MTT assay was evaluated on HCT-116. Clonogenic assay was performed to investigate of radiosensitizing effects of UA and KA on HCT116. To assessment the expression levels of NF-κB and CCND1 genes, real-time PCR method was used. ResultsThe results of MTT assay revealed that UA and KA have cytotoxic effects on HCT116 cell line. According to clonogenic assay, survival fraction of treated cells with UA and KA has been decreased compared to the survival fraction of untreated cells. UA and KA lead to the decrease in the expression level of NF-κB. Synergistic effect of radiosensitizing agents with radiation was only approved for UA and 2 Gy of radiation. ConclusionBased on our study, UA and KA have cytotoxic effects on HCT116 cell line. Furthermore, UA may lead to radiosensitization of human colorectal tumor cells by NF-κB1 and CCND1signaling pathways.

Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exhibit single agent therapeutic activity and sensitize glioblastoma cells to ionizing radiation

Abstract Objective The lack of an effective therapy for glioblastoma (GBM) largely results from the intrinsic resistance of GBM cells. The radiosensitizing activity of inhibitors of poly(ADP-ribose) polymerases (PARPs) highlights the important role of poly(ADP-ribose) (PAR) in the DNA damage response. In contrast to PARPs, inhibition of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for degrading PAR chains, has shown single agent therapeutic activity in non-glioma cancer cells. This work aims to validate the therapeutic potential of PARG inhibitors (PARGi) in GBM. Results Baseline PAR levels were found to vary between different primary and commercial GBM cells, with PARylation increasing upon exposure of cells to ionizing radiation (IR), as expected. Target engagement of a novel PARGi, PDD00017273, was confirmed by the accumulation of nuclear PAR in treated cells. Inhibitor specificity was demonstrated using an inactive control compound and by combining PARGi with the PARP inhibitor olaparib, which blocked the effect. Single agent treatment with PARGi reduced the clonogenic survival of GBM cells in a concentration-dependent manner. Importantly, PARGi also sensitized GBM cells to IR (sensitizer enhancement ratios, SER, ≥ 1.40) Conclusion In contrast to PARP inhibitors, novel PARGi exhibit single agent activity against a panel of GBM cell lines, and also show robust radiosensitizing activity. PARGi therefore have therapeutic potential in this cancer of unmet need.

899TiP - Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N+M0 prostate cancer

BackgroundHigh risk lymph node positive non-metastatic (N+M0) prostate cancer (PCa) patients (pts) are treated with pelvic radiotherapy (RT) and androgen deprivation therapy (ADT), which can lead to significant toxicity. Docetaxel (Doc) has been acknowledged for its radiosensitizing activity. Chemoradiation with RT on the primary tumour could improve local and systemic control, while avoiding toxicity of pelvic RT. This has been investigated in 6 trials with weekly intravenous Doc. Oral chemotherapy is often preferred, improves cost-effectiveness and avoids dexamethasone prophylaxis. However, oral Doc treatment is challenging due to a low systemic uptake. Co-administration of ritonavir (r), a Cyp3A4 and P-glycoprotein inhibitor, and formulation of water soluble tablets (ModraDoc006), increased the bioavailability of orally given Doc (ModraDoc006/r). This phase I study assesses the pharmacokinetics (PK), safety and maximum tolerated dose (MTD) of ModraDoc006/r, given with IMRT and ADT in high risk N+M0 PCa. Trial designHigh risk PCa is defined as newly diagnosed N+M0 disease (>4 radiologic pathologic pelvic lymph nodes), Gleason score ≥4+3=7, ≥cT2c and any PSA, with an indication for (pelvic) RT and ADT. Pts are treated with ADT (28mo), Image-guided Arc Therapy on the primary tumour (77Gy in 35 fractions) and weekly ModraDoc006/r for 7 (Part 1A) or 18 weeks (Part 1B). Sampling for PK of ModraDoc006/r, measured by a validated liquid chromatography with tandem mass spectrometry assay, is done up to 48h after intake. Adverse events (AEs) are evaluated with the National Cancer Institute’s Common Terminology Criteria for AEs and RT Oncology Group/European Organization for Research and Treatment of Cancer scale. Efficacy is assessed by Prostate Specific Antigen and Magnetic Resonance Imaging. In Part 1A, three dose levels are investigated. Dose-escalation is based on acute (within 3mo) and late (within 12mo) dose limiting toxicities (DLTs), evaluated in a Time-to-Event Continual Reassessment Method model. The MTD is the highest dose at which ≤15% of≥6 pts experience DLTs. The number of pts is currently 19 in Part 1A and will be≥9 in Part 1B. Clinical trial identificationNCT03066154. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL). FundingNetherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL). DisclosureJ.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals B.V. All other authors have declared no conflicts of interest.

1123P - A phase I study of the CDK4/6 inhibitor, palbociclib in combination with cetuximab and intensity modulated radiation therapy (IMRT) for locally advanced squamous cell carcinoma of the head and neck (SCCHN); A result of dose escalation cohort

BackgroundHPV induces many alterations in CDK4-Cyclin D-Rb and apoptotic pathways such as up-regulation of p16, loss of Rb and p53 functions in SCCHN carcinogenesis. Loss of p16 expression is known as a poor prognostic marker in SCCHN for survival. Palbociclib is a highly selective inhibitor of CDK4/6 by blocking Rb phosphorylation with radiosensitizing activity in preclinical studies. Addition of palbociclib to cetuximab and IMRT provides a strong rationale to improve efficacy of treatment in locally advanced SCCHN, especially in p16/HPV-negative tumour. MethodsThis is a phase I study designed to determine the maximum tolerated dose (MTD) and toxicity of palbociclib, cetuximab, and IMRT, using a classical 3+3 design (NCT03024489). The study included locally advanced SCCHN of oral cavity, oropharynx, larynx, and hypopharynx. Palbociclib dose was escalated with 3 dose levels (DLs), starting from 75 to 125mg/d orally for 21day-on and 7day-off for 2 cycles. For all DLs, cetuximab was administered at 400mg/m2IV on day -7 and then 250mg/m2weekly for 7 weeks. IMRT was delivered 5day-on and 2day-off with a total dose of 70Gy for 33 fractions. MRI and PET scans pre- and post-treatment was used to evaluate preliminary efficacy. ResultsA total of 13 eligible patients were enrolled in the dose escalation cohort. No MTD was observed. One DLT, febrile neutropenia (FN) was reported in 1 of 7 patients who received 125mg of palbociclib (DL3) at the 6thweek of IMRT. The FN recovered without G-CSF support within 7 days after discontinuation of palbociclib. Overall, toxicities were related to cetuximab and IMRT. Complete response was observed in 7 of 10 evaluable patients (70%), while overall objective response was demonstarted in 9 of 10 patients (90%). ConclusionsThe recommended phase 2 dose was palbociclib 125mg/d for 21 days on and 7 days off with full standard dose of cetuximab and IMRT for locally advanced SCCHN. MTD was not achieved. The combination was well tolerated with promising preliminary efficacy. The expansion cohort of palbociclib 125mg/d is currently accruing up to 15 locally advanced p16-negative SCCHN patients. Clinical trial identificationNCT#03024489. Legal entity responsible for the studyThe authors. FundingPfizer. DisclosureN. Ngamphaiboon: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Boehringer Ingelheim; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Taiho. T. Siripoon: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Boehringer Ingelheim. S. Lukerak: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. N. Sankaseam: Research grant / Funding (institution): Roche; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. E. Sirachainan: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Sanofi/Aventis; Honoraria (self): Merck; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Mundipharma; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): LF Asia; Honoraria (self): Diethelm Keller Logistics; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation.

There is a need for preclinical models that can enable identification of novel radiosensitizing drugs in clinically relevant high-throughput experiments. We used a new high-throughput compatible total cell kill spheroid assay to study the interaction between drugs and radiation in order to identify compounds with radiosensitizing activity. Experimental drugs were compared to known radiosensitizers and cytotoxic drugs clinically used in combination with radiotherapy. VLX600, a novel iron-chelating inhibitor of oxidative phosphorylation, potentiated the effect of radiation in tumor spheroids in a synergistic manner. This effect was specific to spheroids and not observed in monolayer cell cultures. In conclusion, the total cell kill spheroid assay is a feasible high-throughput method in the search for novel radiosensitizers. VLX600 shows encouraging characteristics for development as a novel radiosensitizer.

Effects of Polar Steroids from the Starfish Patiria (=Asterina) pectinifera in Combination with X-Ray Radiation on Colony Formation and Apoptosis Induction of Human Colorectal Carcinoma Cells.

Despite significant advances in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Chemoradiation therapy is a rational approach that has already proven beneficial for several malignancies. However, the existence of toxicity to normal tissue is a serious limitation of this treatment modality. The aim of the present study is to investigate the ability of polar steroids from starfish Patiria (=Asterina) pectinifera to enhance the efficacy of radiation therapy in colorectal carcinoma cells. The cytotoxic activity of polar steroids and X-ray radiation against DLD-1, HCT 116, and HT-29 cells was determined by an MTS assay. The effect of compounds, X-ray, and their combination on colony formation was studied using the soft agar method. The molecular mechanism of the radiosensitizing activity of asterosaponin P1 was elucidated by western blotting and the DNA comet assay. Polar steroids inhibited colony formation in the tested cells, and to a greater extent in HT-29 cells. Asterosaponin P1 enhanced the efficacy of radiation and, as a result, reduced the number and size of the colonies of colorectal cancer cells. The radiosensitizing activity of asterosaponin P1 was realized by apoptosis induction through the regulation of anti- and pro-apoptotic protein expression followed by caspase activation and DNA degradation.

MLTI-02. A PHASE I TRIAL OF SORAFENIB WITH WHOLE BRAIN RADIOTHERAPY (WBRT) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AND A CORRELATIVE FLT-PET BRAIN IMAGING STUDY IN PATIENTS RECEIVING WBRT +/- SORAFENIB

BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.

Doxorubicin-loaded PVP coated Gd2O3 NPs for effective chemoradiotherapy in melanoma

Combination of chemotherapy and radiotherapy (chemoradiotherapy) can synergistically improve the cytotoxic action of chemotherapeutic agents while reducing their side effects. Gadolinium oxide nanoparticles (Gd2O3 NPs) have significant potential as radiosensitizer agents because of their distinctive properties. The surface modification of Gd2O3 NPs with PVP can increase their biocompatibility. The aim of this study was to evaluate the combination of Gd2O3 NPs as radiosensitizer and doxorubicin (DOX) as chemotherapeutic agent to improve cancer chemoradiotherapy. Doxorubicin loaded PVP-coated Gd2O3 NPs (Gd2O3@PVP-DOX NPs) were developed. MTT, and clonogenic assays showed that the viability and surviving fraction of B16F10 melanoma cells were significantly inhibited by treating with Gd2O3@PVP-DOX NPs under radiation compared with treating with the free DOX or PVP-Gd2O3 NPs alone under radiation. Furthermore, significant sensitization occurred with a maximum dose enhancement factor of 2.51 for Gd2O3@PVP-DOX NPs after irradiation. The radiosensitization activity of Gd2O3 NPs and more entrance and retention of DOX in the tumor cells after loading in Gd2O3@PVP-DOX NPs could cause effective inhibition of melanoma tumor cells growth and proliferation. In conclusion, the Gd2O3@PVP-DOX NPs developed in this study could represent a promising strategy for improved cancer chemoradiotherapy in melanoma.

Correlation Between Radiosensitizing Activity and the Stereo-structure of the TX-2036 Series of Molecules.

The stereo-configuration (R-, S-configuration) of chiral-2-nitroimidazole derivatives alters their radiosensitizing activity. This study aimed at examining the molecular features of these enantiomers by molecular simulation techniques. A series of 2-nitroimidazole-based radiosensitizer TX-2036 molecules were synthesized, and their profiles were examined using molecular structural analysis such as conformation analysis, molecular orbital analysis, and electrostatic potential analysis. R-configured TXs (TX-2043, -2030, -2036) had a weaker radiosensitizing activity than S-configured TXs (TX-2044, -2031, -2037), and R-compounds had a small minus electrostatic potential (ESP) field in the cyclopentene-1,3-dione region. S-configured TX-2046 had weaker radiosensitizing activity than R-configured TX-2045, and TX-2046 had a small minus ESP field as well as R-configured TX-2043, -2030, - 2036. The cyclopentene-1,3-dione involved in the small minus ESP field affected the radiosensitizing activity of the TX-2036 series of molecules.

Abstract 3944: MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells

Abstract Although microtubule-associated serine threonine kinase like (MASTL) is an emerging target for selective anticancer treatment, a small-molecule inhibitor of MASTL with antitumor activity had not been reported yet. This study showed the new MASTL inhibitor, MKI 1 (MASTL Kinase Inhibitor 1), with antitumor activity and radiosensitizing effect in breast cancer in vitro and in vivo. MKI 1 was identified and validated its inhibitory activity to MASTL by in silico and in vitro analysis, respectively. MKI 1 inhibited phosphorylated ENSA, a direct substrate of MASTL, but not the other AGC kinases such as Akt signaling in breast cancer cells. In addition, MKI 1 reduced various oncogenic properties of breast cancer cells rather than normal breast cells. Furthermore, MKI 1 increased the radiosensitivity of breast cancer cells and breast cancer stem cells in response to irradiation. We also confirm the in vivo antitumor activity and radiosensitizing effects of MKI 1 in breast tumor xenograft model. Therefore, our results provide the new line of a small-molecule inhibitor of MASTL, MKI 1, with the antitumor and radiosensitizer activity in breast cancer in vitro and in vivo. Citation Format: Ah-Young Kim, Jae-Sung Kim. MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells [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 3944.

Fucoidans from brown algae Laminaria longipes and Saccharina cichorioides: Structural characteristics, anticancer and radiosensitizing activity in vitro

The sulfated α-l-fucans ScF and LlF were obtained from brown algae of the Laminariaceae family (Saccharina cichorioides and Laminaria longipes). According to spectroscopy NMR, the LlF fucan predominantly contained the →3)-α-l-Fucp-(2SO3–)-(1→4)-α-l-Fucp-(1→2)-α-l-Fucp-(4SO3–)-(1→ repeating units, with small amounts of disaccharide 1,4-linked fragments and 3-sulfated fucose residues. Mass spectrometric analysis revealed the presence of the following fragments in the fucan structure: α-l-Fucp-(2SO3–)-(1→4)-α-l-Fucp-(2SO3–)-(1→3)-α-l-Fucp-(4SO3–); α-l-Fucp-(2,4SO3–)-(1→3)-α-l-Fucp-(1→3)-α-l-Fucp-(4SO3–); α-l-Fucp-(2SO3–)-(1→2)-α-l-Fucp; α-l-Fucp-(2SO3–)-(1→2)-α-l-Fucp-(4SO3–); α-l-Fucp-(2SO3–)-(1→3)-α-l-Fucp; α-l-Fucp-(2,4SO3–)-(1→3)-α-l-Fucp; α-l-Fucp-(4SO3–)-(1→4)-α-l-Fucp; and α-l-Fucp-(4SO3–)-(1→4)-α-l-Fucp-(2SO3–). Both ScF and LlF fucoidans inhibited colony formation and growth of melanoma and colon cancer cells and sensitize-tested cancer cells to X-ray radiation to a comparable degree.

Psammaplin A-Modified Novel Radiosensitizers for Human Lung Cancer and Glioblastoma Cells

Background: Psammaplin A (PsA) is a radiosensitizer whereas its clinical application is hampered by poor bioavailability. This study aimed to synthesize novel radiosensitizers using PsA as the lead compound. Materials and Methods: Eight homodimeric disulfides were synthesized from corresponding acid and cystamine dihydrochloride in N-hydroxysuccinimide and dicyclohexylcarbodiimide coupling conditions. One monomeric thiol analog was obtained by reduction of homodimeric disulfide with dithiothreitol. Clonogenic assay was used to measure cell survival after irradiation and drug treatment in human lung cancer (A549) and glioblastoma (U373MG) cells. Results and Discussion: Using the PsA backbone, nine compounds were synthesized. Eight compounds showed variable cytotoxicity with 50% inhibitory concentrations ranging 16.14 μM to 150.10 μM (A549), and 13.25 μM to 50.15 μM (U373MG). Four and six compounds radiosensitized A549 and U373MG cells, respectively. Two compounds that radiosensitized both cell lines were tested for its inhibitory effects on DNMT1. One of them was shown to significantly inhibit DNMT1 activity. Conclusion: Novel compounds with radiosensitizing activity were synthesized. These compounds have a great potential to serve as a basis for the development of future radiosensitizers. Further investigation is warranted for their clinical application.