Side Effects Of Cancer Chemotherapy Research Articles

Natural Phytochemicals Derived from Gymnosperms in the Prevention and Treatment of Cancers.

The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic applications. Paclitaxel is a commercially available anticancer drug derived from gymnosperms. Other natural compounds with anticancer activities, such as pinostrobin and pinocembrin, are extracted from pine heartwood, and pycnogenol and enzogenol from pine bark. Gymnosperms have great potential for further study for the discovery of new anticancer compounds. This review aims to provide a rational understanding and the latest developments in potential anticancer compounds derived from gymnosperms.

Consistency between patients and families in recognizing cancer chemotherapy side effects: A questionnaire survey.

BackgroundAlthough the side effects of cancer chemotherapy impair a patient's quality of life, family members' awareness of side effects may relieve patient anxiety and distress.AimWe investigated whether patients and their families were consistent in recognizing the occurrence and severity of symptomatic side effects of chemotherapy treatment for cancer.Methods and resultsThis was a prospective observational study. We administered a questionnaire survey to patients and family members to assess the frequency of occurrence (1: never, 2: almost never, 3: sometimes, 4: frequently, 5: almost always, 6: unknown) and the degree of severity (1: mild, 2: moderate, 3: severe, 4: extremely severe, 5: unknown) of physical and psychological symptoms associated with cancer chemotherapy. Weighted Kappa and Cramer coefficients were used to assess consistency between the two groups. We surveyed 20 pairs of patients (5 men, 15 women) and their families (10 men, 10 women); 17 pairs lived together. The median age was 65.5 years (interquartile [IQR], 58.75, 69.25) for patients and 61.00 years (IQR, 47.25, 71.25) for family members. Of patients, 17 had solid cancer, and three had leukemia. Family members mostly recognized objectively visible symptoms such as hair loss and development of spots and keratinization. However, it was difficult for families to detect invisible subjective symptoms such as weakness, dysesthesia, depressed mood, and unarticulated anxiety.ConclusionsThe results indicated that recognition of invisible subjective symptoms in patients undergoing chemotherapy was difficult even for family members. Therefore, a multidisciplinary approach in which various medical professionals actively communicate with both patients and families is important. Information sharing in collaboration with patients and families could increase understanding of the patient's condition and optimize patient care.

Microalgae: therapeutic potentials and applications.

Recently, special attention has been paid to marine origin compounds such as carbohydrates, peptides, lipids, and carotenoids, which are extracted from microalgae and have anticancer, anti-inflammatory, antimicrobial (e.g., anti-COVID-19 activity), and antioxidant properties in biomedicine and pharmaceutical biotechnology. In addition, these photosynthetic marine microorganisms have several applications in biotechnology and are suitable hosts for the production of recombinant proteins/peptides, such as monoclonal antibodies and vaccines. Silica-based nanoparticles obtained from diatoms (a microalgae group) are used as drug delivery carriers owing to their biodegradability, easy functionalization, low cost, and simple features compared to synthetics, which make these agents proper alternatives for synthetic silica nanoparticles. Therefore, diatom-based nanoparticles are a viable option for the delivery of anti-cancer drugs and reducing the side-effects of cancer chemotherapy.

Oxaliplatin-related interstitial pneumonia with high-grade fever and relative bradycardia as the presenting signs: a case report

BackgroundAlthough drug-induced interstitial pneumonia is a well-known adverse side-effect of cancer chemotherapy, the disease is difficult to detect in the early phase. We report a case of oxaliplatin-induced interstitial pneumonia in which eosinophilia and high-grade fever with relative bradycardia were useful presenting signs for the early diagnosis.Case presentationA 76-year-old Japanese woman with postoperative recurrent rectal cancer (peritoneal dissemination and liver metastasis) was admitted to our hospital because of productive cough and consolidation on thoracic computed tomography (CT) images. Two months prior to the consultation, she had started chemotherapy (fluorouracil, oxaliplatin, and bevacizumab). After finishing three courses of chemotherapy, she developed fever and was noted to have relative bradycardia. After another two courses of chemotherapy, she developed productive cough, chest discomfort, and high-grade fever. At this time, thoracic CT revealed patchy areas of consolidation distributed predominantly in the periphery. Despite the administration of tazobacterium/piperacillin, the consolidation seen on CT scans gradually worsened. Fiberoptic bronchoscopy was performed, and bronchoalveolar lavage fluid analysis showed increased lymphocytes, eosinophils, and total cell count but a low CD4/ CD8 ratio. No specific pathogen was identified. With a diagnosis of interstitial pneumonia, prednisolone was started and chemotherapy was temporarily discontinued. Her productive cough gradually decreased, and the infiltrative shadows on the thoracic CT scans improved.ConclusionAlthough cases of oxaliplatin-related pneumonia with complicating relative bradycardia are not uncommon, drug-induced interstitial pneumonia should be taken into account in the differential diagnosis. In this case, an increased circulating eosinophil count and high-grade fever with relative bradycardia were the first signs of drug-induced interstitial pneumonia.

CYTOTOXIC POTENTIALS AND PHYTOCONSTITUENTS PROFILING OF BLEPHARIS EDULIS (FORSSK.) PERS. USING UHPLC/Q-TOF-MS-MS

Recently, the demand for discovery of safe anticancer drugs from nature has been extensively increased to avoid cancer chemotherapy side effects. Blepharis edulis (Forssk.) pers (Acanthaceae) is a perennial herb growing in Egypt with many traditional and pharmacological activities. The in vitro assay as well as identification of phytoconstituents in plant samples by LC/MS/MS spectrometry has reserve time and efforts for rapid screening and identification of biologically active compounds in plants. Herein, we investigated the cytotoxic activity of different fractions of Blepharis edulis methanolic extract using Sulforhodamine B stain (SRB) against three cancer cell lines; Hepatocellular carcinoma (HepG-2), human colon carcinoma (HCT-116), and human breast adenocarcinoma (MCF-7) cell lines. The results revealed that the n-butanol fraction showed the most potent cytotoxic activity against the three tested cancer cell lines with CC50 values 9.12 ± 0.92, 6.79 ± 0.65 and 4.19 ± 0.51 against MCF-7, HCT-116 and HepG2 cell lines, respectively. Moreover, the high resolution the ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS-MS) metabolomic analysis for the n-butanol fraction as the most active sample has been achieved for the first time. A total of 30 compound of different classes including flavonoids, aromatic aldehydes, aromatic acids and alkaloids, have been identified from Blepharis edulis.

Dasatinib self-assembled nanoparticles decorated with hyaluronic acid for targeted treatment of tumors to overcome multidrug resistance

Multidrug resistance (MDR) and lack of targeting specificity are the main reasons why traditional drug therapies fail and produce toxic side effects in cancer chemotherapy. In order to increase targeting specificity and maximize therapeutic efficacy, new intelligent drug delivery systems are needed. In this study, we prepared the hyaluronic acid (HA) conjugated dasatinib (DAS) and D-α-tocopherol acid polyethylene glycolsuccinate (TPGS) copolymer nanoparticles (THD-NPs). The water solubility of the hydrophobic drug DAS was improved by chemically linking with HA. HA can bind to the over-expressed CD44 protein of tumor cells to increase targeting specificity, TPGS can inhibit the activity of P-glycoprotein (P-gp), and increase the intracellular accumulation of drugs. The prepared drug-loaded nanoparticle has a particle size of 82.23 ± 1.07 nm with good in vitro stability. Our in vitro studies showed that THD-NPs can be released more rapidly in a weakly acidic environment (pH = 5.5) than in a normal physiological environment (pH = 7.4), which can realize the selective release of nanoparticles in tumor cells. Compared to free drugs, THD-NPs showed more efficient cellular uptake, effectively increased the cytotoxic effect of DAS on nasopharyngeal carcinoma HNE1 cells drug resistance HNE1/DDP cells and increased the accumulation of drugs in HNE1/DDP cells, which may be due to the inhibitory effect of TPGS on the efflux function of P-gp. In vivo experiments showed that THD-NPs can effectively inhibit tumor growth without obvious side effects. In conclusion, the targeted and pH-sensitive nanosystem, we designed has great potential to overcome drug resistance and increase therapeutic effects in cancer treatment.

A Heart-Breast Cancer-on-a-Chip Platform for Disease Modeling and Monitoring of Cardiotoxicity Induced by Cancer Chemotherapy.

Cardiotoxicity is one of the most serious side effects of cancer chemotherapy. Current approaches to monitoring of chemotherapy-induced cardiotoxicity (CIC) as well as model systems that develop in vivo or in vitro CIC platforms fail to notice early signs of CIC. Moreover, breast cancer (BC) patients with preexisting cardiac dysfunctions may lead to different incident levels of CIC. Here, a model is presented for investigating CIC where not only induced pluripotent stem cell (iPSC)-derived cardiac tissues are interacted with BC tissues on a dual-organ platform, but electrochemical immuno-aptasensors can also monitor cell-secreted multiple biomarkers. Fibrotic stages of iPSC-derived cardiac tissues are promoted with a supplement of transforming growth factor-β 1 to assess the differential functionality in healthy and fibrotic cardiac tissues after treatment with doxorubicin (DOX). The production trend of biomarkers evaluated by using the immuno-aptasensors well-matches the outcomes from conventional enzyme-linked immunosorbent assay, demonstrating the accuracy of the authors' sensing platform with much higher sensitivity and lower detection limits for early monitoring of CIC and BC progression. Furthermore, the versatility of this platform is demonstrated by applying a nanoparticle-based DOX-delivery system. The proposed platform would potentially help allow early detection and prediction of CIC in individual patients in the future.

Reactive oxygen species and enzyme dual-responsive biocompatible drug delivery system for targeted tumor therapy

Spurred by newly developed drug delivery systems (DDSs), side effects of cancer chemotherapy could be reduced by using multifunctional nanoplatforms. However, the facile synthesis of effective DDSs remains a challenge. Here, a six-arginine-tailed anti-epidermal growth factor receptor (EGFR) affibody was employed to easily synthesize the highly reactive oxygen species (hROS)- and trypsin-responsive 11-mercaptoundecanoic acid-modified gold nanoclusters (MUA-Au NCs) for tumor-targeted drug delivery. The polyarginine moiety of affibody sealed methotrexate (MTX)-loaded MUA-Au NCs through charge effect, as well as leaving the rest targeting fragment of the affibody to specifically bind tumor overexpressed EGFR. As the shell of MUA-Au NCs-MTX-Affibody (MAMA), polyarginine chains of affibody could be digested by trypsin, helping to release MTX from MAMA. The released MTX accelerated destroying MUA-Au NCs through inducing the generation of hROS. Specifically targeting EGFR-overexpressed tumors, quickly delivering a sufficient amount of drug to the tumor, subsequently increasing the local MTX and hROS levels, and safely eliminating the biocompatible structure from kidney, endowed MAMA greater treatment effectiveness and lower side effect than chemotherapy, especially in pancreatic cancer due to its high trypsin level. This simply fabricated DDS may find applications in high effective cancer therapy, especially for tumors with high trypsin activity.

Astaxanthin ameliorates cisplatin‐induced damage in normal human fibroblasts

AbstractObjectiveOral mucositis is a common adverse side effect of cancer chemotherapy. Its management is of vital importance during cancer treatment. Oxidative stress against normal cells, including epithelial and stromal cells, has been implicated in the pathogenesis of chemotherapy‐induced oral mucositis. Fibroblasts may play a major role in the repair of oral mucosal tissue after chemotherapy. Astaxanthin (AST), a natural xanthophyll carotenoid, has sparked interest because of its strong antioxidant and anti‐inflammatory properties. This study illustrates the protective effects of astaxanthin on normal fibroblasts damaged by chemotherapy.MethodsHuman normal fibroblasts were exposed to cisplatin. The cells were then assessed for cell viability, apoptosis, production of reactive oxygen species, migratory activity, and expression of platelet‐derived growth factor receptors (PDGFRs) in the absence or presence of astaxanthin.ResultsAstaxanthin protected fibroblasts from the side effects of cisplatin, such as reduction in cell viability, apoptotic cell death, generation of reactive oxygen species, reduction in migration activity, and reduced expression of PDGFRs.ConclusionsOur results indicate a broad range of protection from cisplatin damage in fibroblasts by astaxanthin, implying its possible use as a novel therapeutic agent against chemotherapy‐induced oral mucositis.

EFFICACY AND SAFETY OF STANDARDIZED CINNAMON BARK EXTRACT FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED WEIGHT LOSS AND ALOPECIA IN PATIENTS WITH BREAST CANCER: A RANDOMIZED, DOUBLE-BLIND, AND PLACEBO-CONTROLLED STUDY

Objective: The objective of the study was to evaluate the effects of IND02 (standardized Cinnamon bark extract) supplementation for the prevention of side effects of cancer chemotherapy in female patients with breast cancer.
 Methods: The study was conducted using double-blind, placebo-controlled design in 34 female breast cancer patients during the first 4 consecutive 21-day cycles of the standard chemotherapy regimen. The active treatment (IND02 capsules, 400 mg, one capsule, and thrice a day) or matching placebo was orally administrated in randomized (1:1 ratio) patients. The efficacy outcome measures were reduction in chemotherapy-induced weight loss, alopecia (hair fall), and other side effects. The safety outcome measures were hematology, ECG, vital signs, adverse event monitoring, and laboratory safety measurements.
 Results: The patients on the treatment with IND02 had shown significant protection from chemotherapy-induced severe weight loss (cachexia) and alopecia (reduced hair density and % hairs in the anagen phase, and increased % hairs in telogen phase) which was seen in the placebo group. IND02 treatment was found safe and well-tolerated during the study.
 Conclusion: Concomitant use of IND02 in breast cancer patients during breast cancer chemotherapy showed a clinical promise regarding efficacy and safety in preventing chemotherapy-induced weight loss and alopecia.

Integrated Analysis of Clinical and Microbiome Risk Factors Associated with the Development of Oral Candidiasis during Cancer Chemotherapy.

Oral candidiasis is a common side effect of cancer chemotherapy. To better understand predisposing factors, we followed forty-five subjects who received 5-fluorouracil- or doxorubicin-based treatment, during one chemotherapy cycle. Subjects were evaluated at baseline, prior to the first infusion, and at three additional visits within a two-week window. We assessed the demographic, medical and oral health parameters, neutrophil surveillance, and characterized the salivary bacteriome and mycobiome communities through amplicon high throughput sequencing. Twenty percent of all subjects developed oral candidiasis. Using multivariate statistics, we identified smoking, amount of dental plaque, low bacteriome and mycobiome alpha-diversity, and the proportions of specific bacterial and fungal taxa as baseline predictors of oral candidiasis development during the treatment cycle. All subjects who developed oral candidiasis had baseline microbiome communities dominated by Candida and enriched in aciduric bacteria. Longitudinally, oral candidiasis was associated with a decrease in salivary flow prior to lesion development, and occurred simultaneously or before oral mucositis. Candidiasis was also longitudinally associated with a decrease in peripheral neutrophils but increased the neutrophil killing capacity of Candida albicans. Oral candidiasis was not found to be associated with mycobiome structure shifts during the cycle but was the result of an increase in Candida load, with C. albicans and Candida dubliniensis being the most abundant species comprising the salivary mycobiome of the affected subjects. In conclusion, we identified a set of clinical and microbiome baseline factors associated with susceptibility to oral candidiasis, which might be useful tools in identifying at risk individuals, prior to chemotherapy.

Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula \u201cGoshajinkigan\u201d

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-limiting side effects of cancer chemotherapy. Although the control of CIPN is important, it is difficult to manage with currently available therapeutic drugs. Therefore, there is a need for novel therapeutic agents for treating CIPN. Goshajinkigan (GJG) is a Kampo formula composed of ten crude drugs. While GJG has been used for the treatment of CIPN, the active constituents of GJG and their underlying mechanisms of pharmacological effects are still unknown. Our previous study revealed that repetitive oral administration of the water extract of Plantaginis Semen, a crude drug ingredient of GJG, inhibited the mechanical allodynia induced by an intraperitoneal injection of paclitaxel in mice. To elucidate the active compounds of Plantaginis Semen, activity-guided separation of the water extract of Plantaginis Semen was performed. From the active fraction, four iridoids (1–4) were identified. Repetitive oral administration of aucubin (1) at 100 or 30 mg/kg and 100 mg/kg of the fraction crude 3 [primarily comprised of pedicularis-lactone (3)], showed anti-allodynic activity, suggesting 1 and 3 could be some of the active compounds responsible for the anti-allodynic property of Plantaginis Semen and GJG. Our study establishes that oral administration of 1 has potent anti-allodynic effect in addition to the activity of intraperitoneally administered 1 reported previously. Identification of active anti-allodynic compounds found in Kampo formulations will support the development of novel therapies for the management of CIPN in cancer patients.

Cobalt nanowire-based multifunctional platform for targeted chemo-photothermal synergistic cancer therapy

Cobalt nanowires (CoNWs) simultaneously possessing advantages in photothermal effect, targeting drug delivery and photoacoustic imaging property are hopefully promising strategies to further improve the treatment efficiency and reduce the side effects of cancer chemotherapy. Herein, a unique cobalt-based structure decorated with graphene oxide (GO) and polyethylene glycol (PEG) is fabricated through a facile approach. The resultant nanohybrids show relatively low cytotoxicity, favorable biocompatibility as well as inherit the outstanding properties of cobalt. Moreover, CoNWs decorated with GO and PEG (CoNWs-GO-PEG) can load therapeutic drug molecules (e.g., doxorubicin, DOX) with a high drug loading capacity (992.91 mg/g), and simultaneously they are responsive to pH, NIR (near-infrared) irradiation and magnetism stimulation. Accordingly, CoNWs-GO-PEG-DOX shows the satisfactory effect of eliminating cancer cells with synergistic chemo-photothermal therapy in vitro. Current work provides a solid demonstration of the potential of CoNWs-GO-PEG for serving as a targeted antitumor agent in synergistic chemo-photothermal therapy.

Evaluation of efficacy of palonosetron versus ramosetron in patients receiving emetogenic chemotherapy

Background: Chemotherapy induced nausea and vomiting is the most distressing side effect of cancer chemotherapy. It can seriously impact patient’s quality of life, influence the adherence to chemotherapy and progression free survival causing a delay or refusal of potentially life-saving therapy. The objective of this study was to compare the efficacy of palonosetron with ramosetron in achieving complete response to the chemotherapy.Methods: This was a prospective randomized open-label study conducted on 130 patients admitted in Medical Oncology ward of a Tertiary Care Hospitals, Bangalore, India. Patients were randomized to receive either palonosetron 0.25 mg or ramosetron 0.3 mg I.V. along with aprepitant and dexamethasone 30 minutes prior to chemotherapy and were followed up for a period of 5 days post chemotherapy. The observations such as number and severity of vomiting and nausea, the outcome was assessed at the end of 5 days. Pearson’s Chi-square test was used to demonstrate the difference between both the study groups with respect to various categorical data.Results: The complete response rate in delayed phase was more significant in patients who received palonosetron than patients who received ramosetron (72.3% vs 50.8%). Total control was achieved in 38.5% patients with palonosetron as compared to 15.4% patients with ramosetron.Conclusions: Palonosetron is more efficacious than ramosetron in controlling chemotherapy induced nausea and vomiting especially in delayed phase of emesis.

Machine Learning Models for the Prediction of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of cancer chemotherapy that can be life debilitating and cause extreme pain. The multifactorial and poorly understood mechanisms of toxicity have impeded the identification of novel treatment strategies. Computational models of drug neurotoxicity could be implemented in early drug discovery to screen for high-risk compounds and select safer drug candidates for further development. Quantitative-structure toxicity relationship (QSTR) models were developed to predict the incidence of PN. A manually curated library of 95 approved drugs were used to develop the model. Molecular descriptors sensitive to the incidence of PN were identified to provide insights into structural modifications to reduce neurotoxicity. The incidence of PN was predicted for 60 antineoplastic drug candidates currently under clinical investigation. The number of aromatic nitrogens was identified as the most important molecular descriptor. The chemical transformation of aromatic nitrogens to carbons reduced the predicted PN incidence of bortezomib from 32.3% to 21.1%. Antineoplastic drug candidates were categorized into three groups (high, medium, low) based on their predicted PN incidence. QSTR models were developed to link physicochemical descriptors of compounds with PN incidence, which can be utilized during drug candidate selection to reduce neurotoxicity.

Effectiveness of Fosaprepitant in Combination with 5-HT3 Receptor Antagonist and Dexamethasone in Management of Chemotherapy Induced Nausea and Vomiting

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the common side effects of cancer chemotherapy, that affects patient’s physical and psychological aspects, decreasing patients quality of life and compliance with therapy. CINV can be acute, delayed or anticipatory. This study assessed effectiveness of fosaprepitant (NK-1 receptor antagonist) in combination with 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA) plus dexamethasone in prevention and management of nausea and vomiting in patients receiving broad range of chemotherapy regimens.
 Materials and methods: The current study is prospective study conducted on randomly selected 72 patients during first and second cycle of standard chemotherapeutic regimens. During 144 cycles of chemotherapy patients were randomly assigned in two different anti emetic regimen; triplet regimen (aprepitant, 5-HT3 RA, dexamethasone) and duplet regimen (5-HT3 RA, dexamethasone). All the patients were interviewed using MASCC antiemesis tool (MAT) for incidence of nausea and vomiting. Nausea and vomiting was assessed for 5 days following 1st day of each chemotherapy cycle.
 Results: During the period of study, duplet regimen was administered in 68 cycles and triplet regimen was administered in 76 cycles of chemotherapy. Most of the chemotherapy regimen were platinum based compounds (61%). In duplet regimen 76.6 % (52/68) and 72.1% (49/68) patients had acute and delayed vomiting respectively whereas in triplet regimen 7.9% (6/76) and 5.3% (4/76) patients had acute and delayed vomiting respectively. Complete response in triplet regimen were achieved in 89 % of chemotherapy cycles which were significantly low in duplet regimen 10 % only.
 Conclusions: This study concludes that addition of fosaprepitant in combination with 5-HT3 RA and dexamethasone prevents CIMV in cancer patients receiving chemotherapy.

Abstract 2686: Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs

Abstract Triptorelin (TRP) and Leuprorelin (LEP) are two synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in mid 80s. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP and LEP in a combination regiment. Therefore, improving of the biological activity of TRP and LEP by increasing the cellular uptake and retention is a remedy to this end.In this research, polyphenolic derivatives were linked to TRP and LEP through hydrophobic linkers to enhance and optimize the hydrophobicity of these drugs with the expectation to improve the cellular uptake. In this regard, several TRP and LEP conjugates of tris(4-methoxyphenyl)methanol (TPM) derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene, anisole, 2-fluoroanisole or 2-methylanisole and 1,3,5-trioxane, followed by the conjugation with TRP or LEP and decanedioic acid or dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 µM after 24-72 h of incubation. Similar antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-TRP and TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP or LEP. Citation Format: Yousef Beni, Samiyah Alhamed, Jawzah Alnakhli, Kaleh Karim, William Boadi. Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2686.

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT3R and NK1R antagonists.

Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.

Chemotherapy-induced oral mucositis and associated infections in a novel organotypic model.

Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti-neoplastic treatment. There is a lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis because relevant experimental models are non-existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy-induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy-induced mucositis was developed based on a human oral epithelial cell line and a fibroblast-embedded collagen matrix. Treatment of organotypic constructs with 5-fluorouracil (5-FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three-dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5-FU treatment resulted in a widening of epithelial intercellular spaces, characterized by E-cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5-FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5-FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under the conditions tested in this study; however, it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in the pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy.