Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Novel strategies in HPV­16­related cervical cancer treatment: An in vitro study of combined siRNA-E5 with oxaliplatin and ifosfamide chemotherapy.

BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

Gastric Cancer Actively Remodels Mechanical Microenvironment to Promote Chemotherapy Resistance via MSCs-Mediated Mitochondrial Transfer.

Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

Clinical evaluation of oxaliplatin-loaded drug-eluting callispheres beads transarterial chemoembolization for unresectable or recurrent esophageal carcinoma.

BACKGROUND: A majority of esophageal carcinoma patients are diagnosed at an advanced stage and are no longer suitable for surgical resection. Drug-eluting beads transarterial chemoembolization (DEB-TACE) with oxaliplatin-loaded CalliSpheres beads (CB) have been used for advanced hepatocellular carcinoma and lung cancer, but they have not been reported for the treatment of unresectable or recurrent esophageal carcinoma. METHODS: DEB-TACE was performed on 22 patients with unresectable or recurrent esophageal carcinoma between March 2019 and May 2022. The clinical outcomes, complications, and efficacy were retrospectively recorded and analyzed. RESULTS: A total of 39 sessions of DEB-TACE were performed in 22 patients, with a technical success rate of 92.3% and clinical success rate of 65.0%. No severe complications such as procedure-related death, esophageal rupture or paraplegia were observed. Complete response, partial response, and stable disease were observed in 14.3% (2/14), 42.9% (6/14), and 21.4% (3/14) of patients 6 months after DEB-TACE, respectively. The objective response rates were 62.5%, 42.9% and 57.1% respectively at 1-, 3-, and 6-month after DEB-TACE. Subsequent interventional treatments were administered to 12 patients, including DEB-TACE for hepatic metastasis in 3 (13.6%), esophageal stenting in 5 (22.7%), and airway stent placement in 5 (22.7%). Two patients were lost to follow up. A total of 9 patients died due to tumor progression (n = 5), pneumatic infection (n = 1), and tumor-related massive esophageal hemorrhage (n = 3). The median overall survivals were 13.9 months and 26.5 months from the first session of DEB-TACE and the diagnosis of esophageal carcinoma, respectively. CONCLUSIONS: DEB-TACE with oxaliplatin-loaded CB is suggested as a safe and effective treatment of unresectable or recurrent esophageal carcinoma, and more studies are required to confirm its efficacy and safety.

LINC00894 targets Annexin A2 to regulate oxaliplatin resistance in hepatocellular carcinoma: ANXA2 protein function.

To investigate the role of LINC00894 in oxaliplatin chemoresistance of hepatocellular carcinoma (HCC) and its mechanisms. The oxaliplatin-resistant HCC cell lines were established. IC50 of oxaliplatin was calculated by CCK-8 assay. Cell viability was detected using clonal formation experiment, while cell apoptosis was accessed by flow cytometry. RNA binding protein immunoprecipitation and RNA pull-down were performed to explore the interaction of LINC00894 and ANXA2. The expressions of RNA and protein were tested by qRT-PCR and western blot respectively. Tumor xenograft was performed to detect the effect of LINC00894 in vivo. The expression of ki67 was evaluated by immunohistochemistry staining. LINC00894 was overexpressed in HCC cells resistant to oxaliplatin. Elevated LINC00894 promoted HCC cells resistance to oxaliplatin, whereas silence of LINC00894 improved HCC sensitivity to oxaliplatin. LINC00894 could bind to the ANXA2 protein, enhanced the stability of the ANXA2 protein and reduced its ubiquitination. Furthermore, LINC00894 modulated HCC resistance to oxaliplatin both in vitro and in vivo by targeting the ANXA2 protein.LINC00894 enhanced the stability of ANXA2 protein and attenuated its ubiquitination by interacting with it, thereby promoting oxaliplatin resistance in HCC. Our findings contributed to understanding the role of these mechanisms in the process of oxaliplatin resistance in HCC.

LC-MS-based serum metabolomics analysis and potential biomarkers for oxaliplatin induced neurotoxicity in colorectal cancer.

Oxapliplatin-induced peripheral neuropathy (OIPN) is a significant adverse effect encountered in patients with colorectal cancer undergoing oxaliplatin therapy. However, the pathogenesis of OIPN remains unclear. This study aimed to identify potential diagnostic biomarkers for OIPN and discover the metabolic pathways associated with the disease. Serum samples were collected from 218 subjects, including patients with OIPN and control (CONT). The metabolite profiles were analyzed using nontargeted liquid chromatography-mass spectrometry (LC-MS) serum metabolomics method. Subsequently, differentially altered metabolites were identified and evaluated through multivariate statistical analyses. In this study, patients with OIPN and CONT were distinguished by ten significant metabolites. The levels of racemethionine, O-acetylcarnitine, stearolic acid, aminoadipic acid, iminoarginine, galactaric acid, and all-trans-retinoic acid were increased, whereas the levels of 3-methyl-L-tyrosine, 5-aminopentanoic acid, and erythritol compared were found to be diminished in patients with OIPN when compared to the CONT. Through receiver operating characteristic (ROC) curve analysis, racemethionine, stearolic acid, 5-aminopentanoic acid, erythritol, aminoadipic acid, and all-trans-retinoic acid were pinpointed as promising biomarkers for OIPN. Significantly altered pathways included amino acids (arginine biosynthesis, beta-alanine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, lysine degradation, and phenylalanine, tyrosine and tryptophan biosynthesis), lipid (linoleic acid metabolism and the biosynthesis of unsaturated fatty acids), and energy metabolism. This study, by identifying serum biomarkers and dissecting metabolic pathways, offers a groundbreaking perspective on the susceptibility mechanisms underlying OIPN. It stands as an invaluable resource for the adjunctive diagnosis of OIPN, with the potential to diminish the incidence of adverse reactions and to enhance the objectivity and reliability of clinical diagnoses of OIPN.

Impact of oxaliplatin and trastuzumab combination therapy on tumor markers and T lymphocyte subsets for advanced gastric cancer.

BACKGROUND: Advanced gastric cancer (AGC) remains a challenging malignancy with poor prognosis. The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment. This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lymphocyte subsets in patients with AGC and to explore their potential as predictive biomarkers for treatment response. AIM: To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC. METHODS: This prospective study enrolled 60 patients with AGC. All patients received oxaliplatin (130 mg/m2, every 3 weeks) and trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) for six cycles. Serum carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) were measured before and after treatment. T-lymphocyte subsets, including CD3+, CD4+, CD8+, and CD4+ /CD8+ ratios, were also evaluated. The clinical response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: After six cycles of treatment, the CEA, CA19-9, and CA72-4 serum levels significantly decreased compared to baseline levels (P < 0.001). The percentages of CD3+ and CD4+ T lymphocytes increased significantly (P < 0.05), whereas the percentage of CD8+ T lymphocytes decreased (P < 0.05). The CD4+/CD8+ ratio also significantly increased after treatment (P < 0.05). Patients with a higher decrease in serum tumor markers (≥ 50% reduction) and a higher increase in CD4+/CD8+ ratio (≥ 1.5-fold) showed better clinical response rates (P < 0.05). CONCLUSION: Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC. Combination therapy not only has a direct antitumor effect, but also enhances the immune response in patients with AGC. Serum tumor markers and T lymphocyte subsets may serve as potential predictive biomarkers for treatment response in patients with AGC receiving combination therapy.

Unraveling the Spectrum of Ocular Toxicity with Oxaliplatin: Clinical Feature Analysis of Cases and Pharmacovigilance Assessment of the US Food and Drug Administration Adverse Event Reporting System Database.

PURPOSE: Ocular adverse events (oAEs) are a class of adverse events associated with oxaliplatin that are realistically observed in real-world settings. Herein, we aim to describe the clinical characteristics of oAEs associated with oxaliplatin through a systematic review of case reports and to assess a potential safety signal. METHODS: PubMed, Embase, and Cochrane Library databases were used to retrieve case reports. The global disproportionality study was performed leveraging the US Food and Drug Administration Adverse Event Reporting System database from January 2004 to September 2023. Bayesian information component (IC) and reporting odds ratio (ROR) were applied to identify and evaluate potential oAEs associated oxaliplatin. FINDINGS: A total of 20 cases from the systematic case review (of 13 screened articles) were reported on oAEs associated with oxaliplatin, with ages between 26 and 76 years. Therein, 16 (84.2%) cases described loss of vision, and the remaining cases presented with bilateral blepharoptosis, papilledema, and optic disc swelling. Insights from the US Food and Drug Administration Adverse Event Reporting System database showed that oAEs accounted for 4.28% (n = 1194) of the overall oxaliplatin-related adverse event reports, of which 1140 (95.48%) had a serious outcome. The median (interquartile range) onset time of oAEs with oxaliplatin was day 1 (0-25; n = 649). Disproportionality analysis revealed that ocular injuries NEC (n = 28, ROR, 22.72; lower limit of the 95% 2-sided CI for IC, 3.12) was the most significant signals detected. Additionally, unexpected significant oAEs, including eyelid ptosis, eyelid edema, eye movement disorder, blepharospasm, periorbital edema, swelling of eyelid, ophthalmoplegia, retinal vein thrombosis, cataract nuclear, blindness cortical, cataract subcapsular, and lacrimation disorder, were also reported disproportionality. IMPLICATIONS: Our study systematically described the characteristics and outcomes of oxaliplatin-related ocular toxicity and also uncovered potential oAEs that were not disclosed in the package insert. Further prospective epidemiologic studies to validate these findings are warranted.

Oxaliplatin Antibody-Related Thrombocytopenia: A Case Report.

Oxaliplatin is used in combination with fluorouracil and leucovorin as part of the FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen for colorectal cancer (CRC). Oxaliplatin has been shown to cause thrombocytopenia in a majority of CRC patients receiving this drug. Although this thrombocytopenia mainly occurs through myelosuppression, in rare cases, it can be immune-mediated. However, unlike other chemotherapy-induced myelosuppression, oxaliplatin-induced thrombocytopenia presents with a sudden drop within hours to days of oxaliplatin administration. The majority of cases who present with oxaliplatin-induced thrombocytopenia typically present after actively being treated with oxaliplatin. Here, we present the case of a 59-year-old female with biopsy-proven CRC on FOLFOX therapy found to have oxaliplatin antibody-mediated thrombocytopenia. She was originally treated with FOLFOX; however, due to response and clinical symptoms, her regimen was changed to include FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and bevacizumab before reinitiating FOLFOX due to disease progression. During this case, she presented with rectal bleeding and was found to have severe thrombocytopenia. She was treated with platelet transfusion, intravenous immunoglobulin, and steroids for concerns of immune thrombocytopenia; however, through the use of flow cytometry, oxaliplatin and leucovorin antibodies were discovered. Ultimately, oxaliplatin was permanently discontinued due to concerns about further events of thrombocytopenia.

The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways.

The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Recent studies suggest that the two compounds may be working through different mechanisms, with cisplatin inducing cell death via the DNA damage response (DDR) and oxaliplatin utilizing a nucleolar stress-based cell death pathway. While cisplatin-induced DDR has been subject to much research, the mechanisms for oxaliplatin's influence on the nucleolus are not well understood. Prior work has outlined structural parameters for Pt(II) derivatives capable of nucleolar stress induction. In this work, we gain insight into the nucleolar stress response induced by these Pt(II) derivatives by investigating potential correlations between this unique pathway and DDR. Key findings from this study indicate that Pt(II)-induced nucleolar stress occurs when DDR is inhibited and works independently of the ATM/ATR-dependent DDR pathway. We also determine that Pt(II)-induced stress may be linked to the G1 cell cycle phase, as cisplatin can induce nucleolar stress when cell cycle inhibition occurs at the G1/S checkpoint. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461, and find that only Pt(II) compounds cause irreversible nucleolar stress. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress.

Modified FOLFOX6 with Cetuximab versus with Radiotherapy in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: A Single-Center, Prospective, Randomized Controlled Trial.

In this trial, the feasibility and efficacy of neoadjuvant chemotherapy with targeted agents in the treatment of patients with locally advanced rectal cancer were evaluated. In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. We performed a random assignment by a computer-generated random number sequence. The primary end point was the R0 resection rate. The secondary end points were rates of pathologic complete response, downstaging, adverse events, postoperative complications, preventive enterostomy and low anterior resection syndrome. From January 6, 2020 to October 28, 2022, 80 patients were assigned and evaluated. In the mFOLFOX6-RT and mFOLFOX6-Cet groups, the rate of R0 resection was 96.7 and 96.9% (p = 1.000); the rate of pathological complete response (pCR) was 23.3 and 21.9% (p = 0.891); and the rate of downstaging (ypStage 0 to 1) was 53.3 and 53.1% (p = 1.000), respectively. No statistical differences between the two groups were observed in the incidence of adverse events and postoperative complications. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.

Engineering Radiocatalytic Nanoliposomes with Hydrophobic Gold Nanoclusters for Radiotherapy Enhancement.

Chemoradiation therapy is on the forefront of pancreatic cancer care, and there is a continued effort to improve its safety and efficacy. Liposomes are widely used to improve chemotherapy safety, and may accurately deliver high-Z element- radiocatalytic nanomaterials to cancer tissues. In this study, the interaction between X-rays and long-circulating nanoliposome formulations loaded with gold nanoclusters is explored in the context of oxaliplatin chemotherapy for desmoplastic pancreatic cancer. Hydrophobic gold nanoclusters stabilized with dodecanethiol (AuDDT) are efficiently incorporated in nanoliposomal bilayers. AuDDT-nanoliposomes significantly augmented radiation-induced •OH production, which is most effective with monochromatic X-rays at energies that exceed the K-shell electron binding energy of Au (81.7 keV). Cargo release assays reveal that AuDDT-nanoliposomes can permeabilize lipid bilayers in an X-ray dose- and formulation-dependent manner. The radiocatalytic effect of AuDDT-nanoliposomes significantly augments radiotherapy and oxaliplatin-chemoradiotherapy outcomes in 3D pancreatic microtumors. The PEGylated AuDDT-nanoliposomes display high tumor accumulation in an orthotopic mouse model of pancreatic cancer, showing promise for nanoliposomes as carriers for radiocatalytic nanomaterials. Altogether, compelling proof for chemo-radiation dose-enhancement using AuDDT-nanoliposomes is presented. Further improving the nanoliposomal loading of high-Z elements will advance the safety, efficacy, and translatability of such chemoradiation dose-enhancement approaches.

Enhancing sensitivity to oxaliplatin in tongue squamous cell carcinoma: mechanistic insights and therapeutic potential of DHA combination therapy.

Squamous cell carcinoma of the tongue, a common and aggressive malignancy, poses a substantial threat to health and well-being. Despite the promising results of combination therapy with dihydroartemisinin (DHA) and oxaliplatin (Oxa) in various cancers, its effectiveness in treating tongue squamous cell carcinoma had not been explored prior to this study. Our research found that DHA significantly enhances the sensitivity of tongue squamous cell carcinoma cells to Oxa, even at very low concentrations. The combination treatment was observed to modulate the activity of CDK1 and Cyclin B1, arresting the cell cycle in the G2 phase. Additionally, it reduces mitochondrial membrane potential, prompting the release of cytochrome c and activating cleaved caspase-3, which promotes apoptosis. Notably, surface plasmon resonance and immunoprecipitation experiments revealed that DHA targets and attenuates CDK1 modification, weakening its interaction with STAT3 protein. This leads to reduced expression of anti-apoptotic genes and facilitates programmed cell death in CAL-27 cells. The findings underscore the potential of DHA and Oxa as a potent therapeutic strategy for tongue squamous cell carcinoma, opening avenues for clinical application and further exploration into its mechanistic pathways.

Antagonistic roles of cGAS/STING signaling in colorectal cancer chemotherapy.

FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) ß, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8+ T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8+ T cell function. Depletion of cGAS, STING, IRF3, or IFNα/ß receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone. Taken together, our studies have identified a unique pathway leading to chemoresistance and provide a rationale to combine FOLFOX with anti-PD-1/PD-L1 as an effective CRC treatment.

Clinical Efficacy of Hexue Tongbi Formula on Oxaliplatin-Induced Peripheral Neuropathy: A Randomized Controlled Study.

AIM: The aim of this study was to analyse the effiacy of HeXue Tongbi Formula in the treatment of oxaliplatin-induced perpheral neuropathy. METHOD: An open randomized, non-blind, controlled study was conducted at the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from September 2019 to December 2020. A total of 78 maligant tumor patients receiving oxaliplatin-containing chemotherapy were recruited, with half of them receiving HeXue Tongbi Formula for 4 cycles of 21 days. The study assessed the incidence and severity of perpheral neuropathy and the safety of HeXue Tongbi Formula. RESULT: After 4 cycles of treatment, the incidence of perpheral neuropathy in the treatment group was significantly lower than that in the control group (30.77% versus 84.62%, P < .05). The severity of perpheral neuropathy in the treatment group increased sligthly and stabilized from the third cycle, whlie it gradually increased in the control group. yhere were no severe adverse reactions to HeXue Tongbi Formula. CONCLUSION: HeXue Tongbi Formula demonstrated good preventive and therapeutic effects on oxaliplatin-induced perpheral neuropathy. TRIAL REGISTRATION: This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2000032996).

Implications of TRPM3 and TRPM8 for sensory neuron sensitisation.

Sensory neurons serve to receive and transmit a wide range of information about the conditions of the world around us as well as the external and internal state of our body. Sensitisation of these nerve cells, i.e. becoming more sensitive to stimuli or the emergence or intensification of spontaneous activity, for example in the context of inflammation or nerve injury, can lead to chronic diseases such as neuropathic pain. For many of these disorders there are only very limited treatment options and in order to find and establish new therapeutic approaches, research into the exact causes of sensitisation with the elucidation of the underlying mechanisms and the identification of the molecular components is therefore essential. These components include plasma membrane receptors and ion channels that are involved in signal reception and transmission. Members of the transient receptor potential (TRP) channel family are also expressed in sensory neurons and some of them play a crucial role in temperature perception. This review article focuses on the heat-sensitive TRPM3 and the cold-sensitive TRPM8 (and TRPA1) channels and their importance in sensitisation of dorsal root ganglion sensory neurons is discussed based on studies related to inflammation and injury- as well as chemotherapy-induced neuropathy.

Synergizing autophagic cell death and oxaliplatin-induced immunogenic death by a self-delivery micelle for enhanced tumor immunotherapy.

Chemotherapy has become an emerging strategy to activate cytotoxic T cell responses by inducing immunogenic cell death (ICD), but the level of antitumor immunity induced by chemotherapeutic agents, such as oxaliplatin (OXA), is limited due to inadequate tumor antigen presentation and T cell activation. Inducing autophagic cell death (ACD) promotes the release of tumor antigen and the recruitment of dendritic cells, therefore strengthening antitumor immune responses. Here we simultaneously activate ICD and ACD with tumor targeting micelle to achieve enhanced antitumor chemo-immunotherapy. A self-delivery micelle is formulated by conjugating OXA prodrug with tocopherol succinate (TOS) as a hydrophobic segment and further encapsulates autophagy activator SMER28 to afford TOPR/SMER28, which specifically targets αvß3 on tumor cells with c(RGDfK). Upon cellular internalization, OXA is released from the prodrug in response to the high concentration of reduced glutathione (GSH) in tumor cells, triggering ICD and releasing associated molecular patterns (DAMPs) signaling molecules to stimulate immunity. Meanwhile, SMER28 over-activates autophagy to induce autophagic cell death, which further leads to the maturation of dendritic cells and ultimately activates anti-tumor immune response. In the 4T1 tumor-bearing mice, the combination of OXA and SMER28 effectively inhibits tumor growth and activates antitumor immune responses. The tumor targeted micelle releases OXA and SMER28 in an on-demand profile and strengthens tumor chemo-immunotherapy by synergizing ICD and ACD, providing an alternative for antitumor immunotherapy. STATEMENT OF SIGNIFICANCE: Chemotherapy induces immunogenic cell death (ICD) to activate anti-tumor immunity. However, the efficacy is limited by low levels of antigen presentation and T cell activation. To strengthen the antitumor immune responses induced by ICD, we first combine autophagic cell death (ACD) with ICD by formulating a glutathione-responsive oxaliplatin prodrug micelle co-encapsulating the autophagy activator SMER28. The activated autophagic level by SMER28 enhances the release of antigen and the recruitment of APCs, and ultimately bolsters T cell-mediated antitumor immune responses. We provide a potential strategy to amplify antitumor immune effects by combining autophagy activation with chemotherapy.

Ferroptosis-related oxaliplatin resistance in multiple cancers: Potential roles and therapeutic Implications.

Oxaliplatin (OXA)-based therapy is effective in the treatment of multiple cancers. However, primary or acquired OXA resistance remains an emerging challenge for its clinical application. Ferroptosis is an iron-dependent mode of cell death that has been demonstrated to play an essential role in the chemoresistance of many drugs, including OXA. In particular, dysregulation of SLC7A11-GPX4, one of the major antioxidant systems of ferroptosis, was found in the OXA resistance of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). In addition, Nrf2, the upstream regulator of GPX4 and many other antioxidant factors, is also involved in the OXA resistance of CRC and HCC. Inhibition of SLC7A11-GPX4 or Nrf2 by genetic deletion of pharmaceutical inhibition could significantly reverse OXA resistance. Long noncoding RNA (lncRNA) also participates in chemoresistance and ferroptosis of cancer cells. Specifically, LINC01134 promotes the recruitment of Nrf2 to the promoter of GPX4, thereby exerting transcriptional regulation of GPX4, which eventually increases the OXA sensitivity of HCC through upregulation of ferroptosis. On the other hand, a novel lncRNA DACT3-AS1 sensitizes gastric cancer cells to OXA through miR-181a-5p/sirtuin 1(SIRT1)-mediated ferroptosis. Therapies based on ferroptosis or a combination of OXA and ferroptosis enhancers could provide new therapeutic insights to overcome OXA resistance. In the present review, we present the current understanding of ferroptosis-related OXA resistance, highlight ferroptosis pathogenesis in OXA chemoresistance, and summarize available therapies that target OXA resistance by enhancing ferroptosis.

Huaier relieves oxaliplatin-induced hepatotoxicity through activation of the PI3K/AKT/Nrf2 signaling pathway in C57BL/6 mice.

Hepatotoxicity caused by the anticancer medication oxaliplatin (OXA) significantly restricts its clinical use and raises the risk of liver damage. Huaier, a fungus found in China, has been demonstrated to have various beneficial effects in adjuvant therapy for cancer. However, the preventive impact of Huaier against OXA-induced hepatotoxicity is still unknown. The potential molecular pathways behind the hepatoprotective activity of Huaier against OXA-induced hepatotoxicity were investigated in the current study Mice were intraperitoneally injected with 10 mg/kg of OXA once a week for six consecutive weeks to establish a liver injury model. Huaier (2 g/kg, 4 g/kg, and 8 g/kg) was administered weekly to mice by gavage for six weeks. Commercial kits were used to determine the contents of glutathione, catalase, superoxide dismutase, and malondialdehyde. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the impact of Huaier therapy on the expression of the PI3K pathway. Huaier exhibited a good protective effect on OXA-induced hepatotoxicity in a dose-dependent manner, which was connected to the suppression of oxidative stress, according to the results of biochemical index detection and histological staining analysis. In addition, Huaier could counteract the OXA-induced suppression of the PI3K/AKT signaling pathway. Moreover, the hepatoprotective effect and PI3K activation of Huaier were eradicated by LY294002. These findings imply that by decreasing oxidative stress, Huaier can minimize OXA-induced liver injury, establishing the groundwork for Huaier to lessen chemotherapy-induced hepatotoxicity in clinical practice.

Role of TRPA1 in Painful Cold Hypersensitivity.

Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel that plays a pivotal role in pain generation after exposure to irritant chemicals and is involved in the sensation of a wide variety of pathological pain. TRPA1 was first reported to be sensitive to noxious cold, but its intrinsic cold sensitivity still remains under debate. To address this issue, we focused on cold hypersensitivity induced by oxaliplatin, a platinum-based chemotherapeutic drug, as a peculiar adverse symptom of acute peripheral neuropathy. We and other groups have shown that oxaliplatin enhances TRPA1 sensitivity to its chemical agonists and reactive oxygen species (ROS). Our in vitro and animal model studies revealed that oxaliplatin, or its metabolite oxalate, inhibits hydroxylation of a proline residue within the N-terminus of human TRPA1 (hTRPA1) via inhibition of prolyl hydroxylase domain-containing protein (PHD), which induces TRPA1 sensitization to ROS. Although hTRPA1 is insensitive to cold, PHD inhibition endows hTRPA1 with cold sensitivity through sensing the small amount of ROS produced after exposure to cold. Hence, we propose that PHD inhibition can unveil the cold sensitivity of hTRPA1 by converting ROS signaling into cold sensitivity. Furthermore, in this review, we summarize the role of TRPA1 in painful cold hypersensitivity during peripheral vascular impairment.