Chemotherapy-induced Anorexia Research Articles

Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss in rats.

Cancer patients undergoing chemotherapy often experience anorexia and weight loss that substantially deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No notable adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy.

Acupuncture’s Emergence as A Promising Non-Pharmacological Therapy for Appetite Management in Cancer Chemotherapy

Objective The primary objective of this investigation was to assess the impact of acupuncture intervention and explore the intricacies of acupoint selection as a therapeutic strategy for chemotherapy-induced Anorexia (CIA). Method Eight electronic databases were searched to identify relevant studies on the use of acupuncture for the treatment of CIA to conduct a comprehensive meta-analysis. Following this, the Apriori algorithm, correlation analysis, and cluster analysis were performed to identify correlations between the selection of acupoints. Results Acupuncture significantly reduced the incidence of anorexia (RR = 0.76, 95%CI: 0.65, 0.90; I 2=63%; p = 0.001; n = 503) and anorexia score (SMD=-0.33, 95%CI: −0.53, −0.14; I 2=22%; p = 0.0008; n = 419), as well as preserved body mass (MD = 2.70, 95%CI: 1.08, 4.32; I 2=0%; p = 0.001; n = 187) and enhanced physical strength (MD = 4.23, 95%CI: 1.90, 6.55; I 2=58%; p = 0.0004; n = 377). Moreover, subgroup analysis highlighted its efficacy in managing anorexia associated with non-gastrointestinal tumors and mitigating the severity of cisplatin-induced anorexia. Meanwhile, Zusanli (ST36), Neiguan (PC6), Tianshu (ST25), Zhongwan (RN12), and Qihai (RN6) were identified as crucial acupoints in CIA management. Conclusion Acupuncture holds promise as a potential non-pharmacological approach for managing anorexia during cancer chemotherapy. To provide robust evidence of its effectiveness, well-designed Randomized Controlled Trials (RCTs) with larger participant cohorts, and consistent core outcome measures are essential.

Trends in megestrol acetate prescription among Korean patients with biliary-pancreatic cancer and their impact.

85 Background: Chemotherapy-induced anorexia poses a significant challenge for cancer patients, particularly in biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), known for their poor response to treatment. Megestrol acetate (MA), a commonly prescribed appetite stimulant, is associated with concerns regarding thrombosis and polypharmacy. Understanding the trends in MA prescription and its cascade effects is essential for optimizing cancer care. Methods: We conducted a retrospective cohort study using data from the Health Insurance and Review Assessment Service (HIRA) database in South Korea. The study included patients diagnosed with BTC and PDAC between 2008 and 2017. Prescription trends for MA, thrombosis events, anticoagulant prescriptions, and total parenteral nutrition (TPN) were analyzed. Statistical analysis included Chi-square tests and Kaplan-Meier estimates. Results: In our analysis of 41,670 patients with BTC and PDAC between 2008 and 2017, MA prescriptions increased notably, with PDAC patients rising from 7.85% to 51.84%. TPN prescriptions remained consistently high, especially among patients prescribed MA. For instance, in 2008, 94.71% of BTC patients prescribed MA received TPN, compared to 70.34% without MA. Similarly, in 2017, 87.56% of those prescribed MA received TPN, compared to 61.63% without MA. Among BTC patients with long-term MA prescriptions, 16.34% received anticoagulants, compared to 4.92% without MA (p<0.001). Among PDAC patients, 18.3% with long-term MA prescriptions received anticoagulants, compared to 7.12% without MA (p<0.001). Conclusions: The study highlights the escalating trend in MA prescriptions among BTC and PDAC patients, along with increased thrombosis diagnoses and anticoagulant prescriptions. These findings underscore the importance of understanding and managing the cascade effects of MA use and associated polypharmacy in optimizing cancer care and improving patient outcomes.

Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study.

Chemotherapy-induced anorexia is a common occurrence in patients undergoing treatment for advanced lung cancer. However, the relationship between chemotherapy-induced anorexia and weight loss during platinum-based chemotherapy combined with immune checkpoint inhibitors is unclear. This study explored the relationship between chemotherapy-induced anorexia and therapeutic outcomes in patients with stage IV non-small-cell lung cancer undergoing platinum-based chemotherapy combined with immune checkpoint inhibitors. The study retrospectively reviewed the medical records of 106 patients with stage IV non-small-cell lung cancer treated with platinum-based chemotherapy and immune checkpoint inhibitors between January 2019 and October 2022. The incidence of weight loss and its association with treatment efficacy was assessed in the chemotherapy-induced anorexia group. Chemotherapy-induced anorexia, nausea, and vomiting were evaluated using Common Terminology Criteria for Adverse Events v 5.0. Progression-free and overall survival were used to measure treatment efficacy. Chemotherapy-induced anorexia was observed in 13.2% of patients. These patients exhibited significant weight loss at 6 and 9 weeks after treatment initiation compared to those in the non-chemotherapy-induced anorexia group. Progression-free and overall survival were shorter in the chemotherapy-induced anorexia group than in the non-chemotherapy-induced anorexia group, but the difference was not statistically significant. Chemotherapy-induced anorexia was associated with significant weight loss and reduced treatment efficacy in patients with stage IV non-small-cell lung cancer. These results highlight the importance of implementing robust supportive care for chemotherapy-induced anorexia to mitigate weight loss and uphold treatment effectiveness during platinum-based chemotherapy combined with immune checkpoint inhibitors.

Liujunzi decoction attenuates cisplatin-induced anorexia in rats via inhibiting PERK/eIF2α/ATF4/CHOP pathway and GDF15/GFRAL expression

Background and aimLiujunzi Decoction (LJZD), also called Rikkunshito, is a traditional formula that has proven effective in clinical treatment against chemotherapy-induced anorexia (CIA). Previous study indicated the importance of GDF15/GFRAL axis in the pathogenesis of CIA, and suggested the potential connection between endoplasmic reticulum stress and GDF15 expression. However, further exploration is required to determine whether the mechanism of LJZD against CIA is related to the PERK/eIF2α/ATF4/CHOP signaling and GDF15/GFRAL expression. MethodsThe CIA model of rats was established via intraperitoneal injection of cisplatin, and the rats were given LJZD orally for 72 ​h. Food intake and body weight were recorded daily. The expression of GDF15/GFRAL and ER stress factors, as well as the histological injuries were investigated. ResultsLJZD led to a significant increase in food intake in rats and a decrease in serum GDF15 levels at 24 ​h and 72 ​h after cisplatin injection. This effect may be associated with the inhibition of Gdf15 transcription and the amelioration of pathological injuries or endoplasmic reticulum stress in the liver and ileum. Moreover, LJZD suppressed the cisplatin-induced activation of the hepatic and ileal PERK/eIF2α/ATF4/CHOP pathway, resulting in the alleviation of central GDF15/GFRAL expression. ConclusionLJZD effectively improves cisplatin-induced anorexia in a rat model, which might be attributed to its inhibition of the PERK/eIF2α/ATF4/CHOP pathway and GDF15/GFRAL expression activated by cisplatin.

Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

A taste alteration-related scale assesses megestrol to improve chemotherapy-induced anorexia.

We evaluated the efficacy of megestrol in improving chemotherapy-related anorexia by analyzing the related scales of taste alteration. We conducted the current study on a group of advanced patients with cancer with two or more chemotherapy cycles. The chemotherapy-induced taste alteration scale (CiTAs) scale helped assess the megestrol effects on basic taste perception, aversive taste changes, unpleasant symptoms, and associated concerns. Furthermore, the Short Nutritional Assessment Questionnaire scale (SNAQ) helped measure the impact of megestrol on malnutrition likelihood in patients experiencing chemotherapy-induced anorexia. The World Health Organization Quality of Life (WHOQOL)-BREF Scale was used to evaluate the quality of life of participants, producing scores related to physical health, psychological well-being, environmental factors, and social relationships. The CiTAs scale assessment indicated that administering megestrol significantly enhanced taste perception among advanced patients with cancer undergoing chemotherapy. Notably, the megestrol group patients showed significantly higher Short Nutritional Assessment Questionnaire (SNAQ) scores than the control group. The megestrol group patients also exhibited higher physiological (PHYS) scores than their control group counterparts. However, this distinction was not statistically significant. The study findings indicate that patients who received megestrol demonstrated significantly higher scores in psychological (PSYCH) and environmental(ENVIR) domains than the control group. Furthermore, megestrol administration was associated with significantly elevated SOCIL and ENVIR levels in patients. The proficient efficacy evaluation of megestrol in enhancing appetite, mitigating malnutrition likelihood, and improving the quality of life of chemotherapy-induced anorexic patients can be achieved through taste-related scales.

Liu-Jun-Zi decoction alleviates chemotherapy-induced anorexia by regulating gut microbiota and TLR4/MyD88/NF-κB p65 signaling pathway

Liu-Jun-Zi decoction alleviates chemotherapy-induced anorexia by regulating gut microbiota and TLR4/MyD88/NF-κB p65 signaling pathway

Effect of melanocortin-4 receptor antagonist TCMCB07 on chemotherapy-induced anorexia and weight loss in rats.

e15196 Background: We previously reported that peripheral administration of TCMCB07, a synthetic antagonist of the type 4 melanocortin receptor (MC4R), ameliorates cancer- and chronic kidney disease-associated cachexia in rats. In this study, we used a rat model of cisplatin and 5-FU to evaluate the efficacy of TCMCB07 in alleviating chemotherapy-induced anorexia, weight loss and muscle wasting. Methods: Two separate experiments were performed in a total of 58 rats. 1) Cisplatin (Cis)/TCMCB07 experiment with 3 groups: Cis/saline (n = 11), Cis/TCMCB07 (n = 11), Saline/saline (n = 6). 2) 5-FU/TCMCB07 experiment with 3 groups: 5-FU/saline (n = 12), 5-FU/TCMCB07 (n = 12), Saline/saline (n = 6). Rats were treated with Cis (2.5mg/kg), 5-FU (70 mg/kg), or saline via IP injection once weekly for 3 weeks. Rats were also treated with TCMCB07 (3 mg/kg/day) or saline via daily SC injection for 21 days. Food intake and body weight were measured daily. Body composition was analyzed pre- and post-treatment by MRI. Heart and gastrocnemius were dissected and weighed after euthanasia. Results: Total food intake over 21 days was significantly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0006) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0134), and decreased in Cis/saline vs Saline/saline group (p = 0.001), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/saline or 5-FU/TCMCB07 vs Saline/saline group. Body weight was robustly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0007) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0013), and decreased in Cis/saline vs Saline/saline group (p = 0.0001) and 5-FU/saline vs Saline/saline group (p = 0.0041), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/TCMCB07 vs Saline/saline group. Cardiac and skeletal muscle loss was markedly attenuated in Cis/TCMCB07 vs Cis/saline (cardiac: 3.12% vs -11.95%, p < 0.0001; skeletal: -3.88% vs -9.02%, p = 0.0259). Cardiac muscle loss was significantly attenuated in 5-FU/TCMCB07 vs 5-FU/saline group (1.40% vs -6.09%, p = 0.0131) and skeletal muscle was modestly changed (-4.17% vs -7.24%, p = 0.1782). While Cis/saline and 5-FU/saline groups lost 91.33% and 52.61% of fat mass respectively compared to Saline/saline group, Cis/TCMCB07 and 5-FU/TCMCB07 groups gained 37.68% (p = 0.0002) and 70.19% (p < 0.0001). Conclusions: This preclinical trial provides evidence supporting peripheral TCMCB07 antagonism of central melanocortin signaling, increasing food intake and anabolism, ultimately alleviating anorexia, weight loss and muscle wasting over multiple cycles of cisplatin or 5-FU chemotherapy.

Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

Research Progress of Liujunzi Decoction in the Treatment of Tumor-Associated Anorexia.

Tumor-associated anorexia, mainly including cancerous anorexia and chemotherapy-induced anorexia, severely reduces the life quality of cancer patients but lacks of effective control until now. Liujunzi decoction (LJZD), a classical tonifying formula in traditional Chinese medicine, has promising effect in preventing and treating many kinds of anorexia. A growing number of evidence showed that LJZD is able to improve tumor-associated anorexia. Up to March 2022, a total of 58 articles studying LJZD or Rikkunshito (the name of LJZD in Japanese herbal medicine) in the treatment of tumor-associated anorexia are searched out in PubMed. This paper summarizes the effect of LJZD in ameliorating tumor-associated anorexia, in order to provide a theoretical basis for the clinical application of LJZD in treating tumor-associated anorexia, laying foundation for further research.

Multievaluation Strategy for Liujunzi Decoction: Fingerprint Characterization, Chemometrics Analysis, Network Pharmacology, and Molecular Docking

Liujunzi decoction (LJZD), a traditional tonic formula for treating “qi” deficiency of the spleen and the syndrome of phlegm dampness, can be used to prevent and treat chemotherapy-induced anorexia (CIA). The chemical constituents of LJZD are rather complex; therefore, it is of great significance to establish an effective and economic quality control method to ensure the quality consistency and stability of LJZD. With one chromatographic condition, 13 common peaks detected at 203 nm were selected to establish a fingerprint similarity model and 7 chemical constituents were identified as ephedrine hydrochloride, liquiritin, hesperidin, ginsenoside Rg1, jujuboside A, 6-gingerol, and atractylenolide III. Ten batches of LJZD were divided into two groups by cluster analysis and principal component analysis (PCA), and four main components (ephedrine hydrochloride, hesperidin, ginsenoside Rg1, and jujuboside A) of LJZD were analyzed. Also, the analysis results were combined with network pharmacology and molecular docking technology to further predict how LJZD could prevent and treat CIA. We found that these four main components of LJZD spontaneously combined with four CIA targets (SRC, PIK3R1, MAPK1, and AKT1). In this study, we established the fingerprint of LJZD for the first time, and through a comprehensive multiassessment method, we also successively analyzed the fingerprint and chemometrics.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats

Ethnopharmacological relevanceAs a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). Aim of the studyThe present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. Materials and methodsNetwork pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. ResultsNetwork pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. ConclusionThis study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Endothelial peroxynitrite causes disturbance of neuronal oscillations by targeting caspase-1 in the arcuate nucleus

Severe anorexia limits the clinical application of cisplatin, and even leads to the discontinuation of treatment. However, the mechanisms underlying cisplatin-induced anorexia are unknown. Herein, we demonstrated that cisplatin could affect neuronal gamma oscillations and induce abnormal neuronal theta-gamma phase-amplitude coupling in the arcuate nucleus (Arc) of the hypothalamus, and these findings were associated with significantly decreased food intake and weight loss in mice. Chemogenetic activation of AgRP neurons in the Arc reversed the cisplatin-induced food intake reduction in mice. We further demonstrated that endothelial peroxynitrite (ONOO−) formation in the Arc induced nitrosative stress following cisplatin treatment via a previously uncharacterized pathway involving neuronal caspase-1 activation. Strikingly, treatment with the ONOO− scavenger uric acid (UA) reversed the reduced action potential (AP) frequency of AgRP neurons and increased the AP frequency of POMC neurons induced by SIN1, a donor of ONOO−, in the Arc, as determined by whole-cell patch-clamp electrophysiological recording. Consistent with these findings, UA treatment effectively alleviated cisplatin-induced dysfunction of neuronal oscillations and neuronal theta-gamma phase-amplitude coupling in the Arc of mice. Taken together, these results suggest, for the first time, that targeting the overproduction of endothelial ONOO− can regulate cisplatin-induced neurotoxicity through neuronal caspase-1, and thereby serve as a potential therapeutic approach to alleviate chemotherapy-induced anorexia and weight loss.

The Ciji-Hua'ai-Baosheng II Formula Attenuates Chemotherapy-Induced Anorexia in Mice With H22 Hepatocellular Carcinoma.

Background: Ciji-Hua’ai-Baosheng II Formula (CHB-II-F) is a traditional Chinese medicine formula, which specifically targets different aspects of chemotherapy-induced adverse effects in patients with cancer. In our clinical application, CHB-II-F significantly alleviated chemotherapy-induced anorexia (loss of appetite) and improved the quality of life for patients with tumor during and after chemotherapy. However, the mechanism of CHB-II-F in alleviation of chemotherapy-induced anorexia remains to be further investigated.Aim of Study: To explore the therapeutic effect and mechanism of CHB-II-F on chemotherapy-induced anorexia in the mice model of H22 hepatoma.Materials and Methods: A total of 72 Kunming mice of SPF grade were inoculated subcutaneously with H22 hepatoma cells into the right anterior armpit of the mice. After 1 week of seeding, mice were injected intraperitoneally with a high dose of 5-fluorouracil (200 mg/kg 5-FU) to establish the model of chemotherapy. The mice were randomly divided into six groups: untreated group, 5-FU group, 5-FU plus Yangzheng Xiaoji capsule (YZXJC) group, and three groups of 5-FU plus different concentrations of CHB-II-F. All the mice in each group were treated for 14 days. The body weight, food intake, tumor volume, and tumor weight of mice were measured, and pathological examinations of tumor tissue, stomach, and duodenum were carried out. Expressions of serum Leptin, Neuropeptide Y (NPY), epidermal cell growth factor (EGF), Motilin (MTL), Orexin A (OXA), Gastrin (GAS), Ghrelin, Prostaglandin E2 (PGE2), and jejunum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were examined. The protein and mRNA levels of proopiomelanocortin (POMC), Orexin receptor 1 (OX1R), neuropeptide Y (NPY), cocaine and amphetamine regulated transcript peptide (CART), Agouti gene-related protein (AgRP), Leptin receptor (Ob-R), and Ghrelin receptor (GHSR) were examined in hypothalamus, and the protein levels of substance P (SP) and 5-hydroxytryptamine (5-HT) in duodenum were measured.Results: The combination of CHB-II-F and 5-FU could enhance the inhibitory effect of 5-FU on tumor. The tumor inhibition rates of 5-FU group, YZXJC group, CHB-II-F(H) group, CHB-II-F(M) group, and CHB-II-F(L) group were 58.88, 28.08, 54.96, 37.69, and 28.61%, respectively. Compared with untreated group and 5-FU group, CHB-II-F significantly increased the body weight and food intake of tumor-bearing mice; increased the content of NPY, Orexin A, Ghrelin, GAS, MTL, EGF, and PGE2 in serum and the activity of SOD in jejunum; and decreased the content of Leptin in serum and the content of MDA in jejunum. Compared with untreated group and 5-FU group, CHB-II-F also enhanced the expression of OX1R, GHSR, NPY, and AgRP protein and gene and decreased the expression of Ob-R, POMC, and CART protein and gene in hypothalamus of mice, and the gene expression was consistent with the protein expression. In addition, CHB-II-F decreased the expression of 5-HT and SP protein in duodenum.Conclusion: In the murine model of H22 hepatocellular carcinoma (HCC) receiving chemotherapy, CHB-II-F enhances the inhibitory effect of 5-FU on tumor, significantly improves the pathological injury of gastrointestinal tract caused by chemotherapy, and regulates the secretion of gastrointestinal hormones. It may alleviate chemotherapy-induced anorexia by affecting appetite regulatory factors in the feeding area of hypothalamus central nervous system and peripheral appetite regulatory factors.

Abstract 3056: Growth differentiation factor 15 (GDF-15) inhibition attenuates platinum-based chemotherapy-induced emesis, anorexia and weight loss and increases survival

Abstract Platinum-based chemotherapy is associated with nausea/emesis, anorexia and weight loss which reduce patient quality of life and limit treatment adherence potentially leading to poor treatment outcomes. Cisplatin increases circulating growth differentiation factor 15 (GDF-15), a cytokine that induces conditioned taste aversion, anorexia and weight loss in preclinical models. GDF-15 signals through the hindbrain receptor glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). Cisplatin-induced anorexia/weight loss was attenuated in a GFRAL knockout mouse; therefore, we examined whether GDF-15 inhibition can prevent platinum-based chemotherapy-induced emesis, anorexia and weight loss, and also increase survival using mouse and/or nonhuman primate models. In cancer patients, platinum treatment increased circulating GDF-15 in non small cell lung carcinoma, colorectal, and ovarian cancer (~1.5 fold) compared to those receiving a non-platinum-based therapy. Furthermore, cisplatin, oxaliplatin and carboplatin administered individually all increased circulating GDF-15 in wildtype mice (≥ 5 fold) and induced anorexia, skeletal muscle wasting, and weight loss. GDF-15 mRNA was increased in kidney, liver, brain and white adipose tissue. These effects were prevented in GDF-15 knockout mice, however only a partial blockade was observed in the carboplatin group. In nonhuman primates, cisplatin treatment for 5 days (96% of the daily recommended clinical dose) also increased circulating GDF-15 (> 5 fold), and induced anorexia and emesis. Treatment with the anti-GDF-15 monoclonal antibody (mAB1) resulted in no detectable circulating levels of free GDF-15, and attenuated both cisplatin-induced anorexia and emesis. Furthermore, in a mouse cachectic tumor model (subcutaneous implantation of tumor tissue derived from human non-small cell lung carcinoma adenocarcinoma), cisplatin treatment inhibited tumor growth; however, GDF-15 levels were still elevated and additional weight loss occurred compared to vehicle control. When mAB1 was given in combination with cisplatin, weight loss was reversed and tumor growth inhibition was maintained, resulting in greater survival compared to cisplatin alone. Taken together, these data support the notion that GDF-15 inhibition with mAB1 holds the potential as an effective therapeutic approach to alleviate GDF-15 mediated emesis, anorexia and weight loss with the aim to enable optimal cancer treatment as well as to improve patient quality of life and potentially survival. Citation Format: Danna M. Breen, Kevin Beaumont, Donald Bennett, Julia Brosnan, Roberto Calle, Jeffrey R. Chabot, Susie Collins, Teresa Cunio, Ryan M. Esquejo, Stephanie Joaquim, Alison Joyce, Hanna Kim, Laura Lin, Betty Pettersen, Shuxi Qiao, Michelle Rossulek, Brendan Tierney, Karen M. Walters, Gregory Weber, Zhidan Wu, Bei B. Zhang, Morris J. Birnbaum. Growth differentiation factor 15 (GDF-15) inhibition attenuates platinum-based chemotherapy-induced emesis, anorexia and weight loss and increases survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3056.

GDF15 Induces Anorexia through Nausea and Emesis

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and hasbecome a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry.

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5g/day for 14days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Metabolites as mediator for alleviating adverse effects in chemotherapy: A new finding from a recent study of Japanese traditional Kampo medicine, rikkunshito (RKT).

e18292 Background: In Japan, RKT is used for chemotherapy-induced anorexia. There is considerable variation in the therapeutic response to RKT. We assessed the efficacy of RKT on anorexia induced by cisplatin (CDDP) therapy in lung cancer patients (pts) from the clinical and the plasma metabolomics perspectives. Methods: The study was a double-blind, randomized trial evaluating pts with age ≥20 y with lung cancer assigned to receive regimen including CDDP, ECOG PS 0 to 1. Pts were administered RKT or placebo from the beginning of 1st course of chemotherapy (Day1) until just before starting the 2nd course (21 or 28 consecutive days). The clinical endpoints were the change in mean dietary intake in hospital (MDIH), QOL and nutritional indices. Plasma samples were collected at Day1, Day7 and Day22 (22nd or 29th day) for metabolome analyses. Results: 60 pts were enrolled between Nov 2014 and Aug 2017. 29 were allocated to RKT and 31 to placebo. The ANCOVA estimate of treatment effect in MDIH (baseline adjusted RKT-Placebo difference) was not significant (-6.7; 95% C.I. -61.1 to 47.8). Regarding QOL, there was no significant results in changes of QLQ-C30 Global Health Status. Among the related subscales, Pain in Day22 in PPS analysis was the only significant item (-17.0; -29.7 to -4.2). Regarding QLQ-LC13 , Alopecia in Day22 was the only significant item (-21.3; -36.9 to -5.8). The changes in nutritional indices did not show any significant difference, either. In metabolome analysis, CDDP drastically influenced metabolites, such as essential amino acids. RKT did not significantly change them compared to the placebo. In contrast, the changes of acetylglycine and arabinose in plasma strongly correlated with those in dietary intake and pain only in the RKT. Conclusions: In this exploratory study, no significant difference was observed in the MDIH. Although, pain and alopecia observed in QOL were significantly improved in the RKT. Some plasma metabolites were found to correlate with improvement in dietary intake or QOL. This is the first suggestive evidence that the efficacy of RKT would be variable depend on the metabolic profile. Clinical trial information: JAPIC CTI-142747.

Electroacupuncture for chemotherapy-induced anorexia through humoral appetite regulation: A preliminary experimental study.

Chemotherapy-induced anorexia (CIA), which may lead to severe nutrition-associated problems, is a common complication associated with anti-cancer therapies. In the present study, the anti-anorexigenic effect of electroacupuncture (EA) was explored through assessing a change in appetite-associated peptides and c-Fos expression in a rat model of cisplatin-induced anorexia. In order to identify the most effective acupuncture point, 20 male Wistar rats (divided into five groups including the normal saline control, cisplatin only control and three groups according to the acupoints stimulated) were subjected to EA for 10 min at CV12, ST36 or PC6 daily for 4 days. Subsequently, the rats received intraperitoneal injections of cisplatin (6 mg/kg) to induce CIA. Food intake and reduction in body weight gain as the anorexia-associated outcomes were assessed daily for up to 3 days after cisplatin injection, and CV12 was eventually chosen as the most effective acupoint to test the anti-anorexigenic effect of EA. Furthermore, food intake, body weight and the concentrations of appetite-associated peptides, including ghrelin, cholecystokinin (CCK) and 5-hydroxytryptamine (5-HT), in addition to c-Fos expression, were comparatively assessed between the CV12 EA group (n=6; rats treated with EA at CV12 daily for 4 days) and a control group (n=6; rats without treatment). The results indicated that the CV12 EA group exhibited a better outcome regarding food intake and body weight compared with the controls. Although there was no statistically significant difference observed, the secretion of serum ghrelin and CCK was increased in the CV12 EA group compared with that in the control group. The plasma level of 5-HT after cisplatin injection in the CV12 EA group was lower compared with that in the control, although no statistical significance was reached. Although not statistically significant, the expression of c-Fos protein in the nucleus tractus solitarius (NTS) was reduced in the CV12 EA rats. In addition, the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF) were significantly increased in the CV12 EA group. In the hypothalamus, the expression of neuropeptide Y mRNA slightly increased in the cisplatin + CV12 EA group compared with the cisplatin only control group. In conclusion, the anti-anorexigenic effect of EA on CIA may be associated with an increase in the secretion of ghrelin and CCK and a decrease in the secretion of 5-HT into the serum, a reduction of c-Fos expression in the NTS and an increase in BDNF mRNA expression in the hypothalamus.