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.

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.

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.

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.

Platinum Deposition in the Central Nervous System: A Novel Insight into Oxaliplatin-induced Peripheral Neuropathy in Young and Old Mice.

Numerous factors can contribute to the incidence or exacerbation of peripheral neuropathy induced by oxaliplatin (OXA). Recently, platinum accumulation in the spinal cord of mice after OXA exposure, despite the efficient defenses of the central nervous system, has been demonstrated by our research group, expanding the knowledge about its toxicity. One hypothesis is platinum accumulation in the spinal cord causes oxidative damage to neurons and impairs mitochondrial function. Thus, the main aim of this study was to investigate the relationship between aging and OXA-induced neuropathic pain and its comorbidities, including anxious behavior and cognitive impairment. By using an OXA-induced peripheral neuropathy model, platinum and bioelement concentrations and their influence on oxidative damage, neuroprotection, and neuroplasticity pathways were evaluated in Swiss mice, and our findings showed that treatment with OXA exacerbated pain and anxious behavior, albeit not age-induced cognitive impairment. Platinum deposition in the spinal cord and, for the first time, in the brain of mice exposed to OXA, regardless of age, was identified. We found that alterations in bioelement concentration, oxidative damage, neuroprotection, and neuroplasticity pathways induced by aging contribute to OXA-induced peripheral neuropathy. Our results strive to supply a basis for therapeutic interventions for OXA-induced peripheral neuropathy considering age specificities.

Hydrogel based on M1 macrophage lysate and alginate loading with oxaliplatin for effective immunomodulation to inhibit melanoma progression, recurrence and metastasis.

Despite the monumental success of immunotherapy in treating melanoma clinically, it still confronts significant challenges, chiefly that singular immunomodulatory tactics are insufficient to suppress the recurrence and metastasis of melanoma. Herein, these challenges are addressed by a hydrogel based on M1 macrophage lysate and alginate (M1LMHA) loaded with oxaliplatin (OXA), named M1LMHA@OXA.The results obtained from scanning electron microscopy and confocal microscopy indicate that the structure and morphology of M1LMHA@OXA remain unchanged. Flow cytometry results reveal that M1LMHA@OXA significantly promotes the maturation of dendritic cells (DCs) and enhances the proliferation of T lymphocytes. In a subcutaneous melanoma transplant model, M1LMHA@OXA effectively suppressed tumor growth in comparison to OXA alone and M1LMHA alone. Flow cytometry demonstrated that M1LMHA@OXA markedly increased the number of mature DCs and CD8+ T cells at the tumor site, while significantly reducing the quantity of M2-like tumor-associated macrophages (TAM) and enhancing the presence of M1 macrophages. Enzyme-linked immunosorbent assay (ELISA) results indicated that following treatment with M1LMHA@OXA, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the bloodstream of mice were significantly elevated, whereas interleukin-10 (IL-10) exhibited no significant difference. This outcome further corroborates the ability of M1LMHA@OXA to substantially bolster the immune capability of mice. Similar results have also been observed in a melanoma subcutaneous transplantation recurrence model, and optical imaging of the lungs of mice revealed that M1LMHA@OXA inhibited tumor metastasis to the lungs. Notably, M1LMHA@OXA exhibits an exceptional therapeutic effect on the growth, post-surgical recurrence, and metastasis of the B16F10 melanoma. Therefore, this study provides a straightforward strategy that leverages the cooperative regulation of multiple immune cells to thwart the proliferation, recurrence, and spread of melanoma.

Oxaliplatin activates P53/miR-34a/survivin axis in inhibiting the progression of gastric cancer cells.

INTRODUCTION: The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer. METHODS: The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined. RESULTS: In the 12- and 24-h groups, drug concentration of 15 µg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively). CONCLUSION: Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells.

circ_0006089 facilitates gastric cancer progression and oxaliplatin resistance via miR-217/NRP1.

BACKGROUND: Oxaliplatin (OXA) is a vital tool in the chemotherapy of gastric cancer (GC) patients. Circular RNAs (circRNAs) are a group of non-coding RNAs that have been associated with tumorigenesis. Nevertheless, the function of circRNAs in OXA resistance of GC is unknown. METHODS: Circ_0006089/miR-217/NRP1 were elucidated through qRT-PCR in GC OXA-tolerant tissues and cell lines. OXA half-inhibitory concentration (IC50) was quantified by MTT assay. RNA pull-down and luciferase reporter tests were applied to characterize the interaction between circ_0006089 and miR-217, miR-217 and NRP1 in GC cells. RESULTS: The findings disclosed that circ_0006089 and NRP1 was heightened whereas miR-217 was dramatically declined in OXA-tolerant GC tissues and cell lines. OXA resistance was reduced and the proliferation, migration and invasion ability of OXA cells were diminished after silencing circ_0006089. In addition, circ_0006089 raised OXA resistance by sponging miR-217. Further studies revealed that miR-217 bound to NRP1 and weakened OXA resistance. In addition, it was found that circ_0006089 accelerated GC progression and OXA resistance by upregulating NRP1 expression via sponging miR-217. CONCLUSION: Circ_0006089 regulated OXA resistance in GC cells through miR-217/NRP1 axis, implying it was a promising biomarker for GC therapy.

Statins ameliorate oxaliplatin- and paclitaxel-induced peripheral neuropathy via glutathione S-transferase.

Some therapeutic agents have been found to have effects beyond their primary indications. Peripheral neuropathy, a common side effect of chemotherapy, remains inadequately treated. Identifying additional properties of existing medications could thus uncover novel therapeutic avenues. Previous studies have identified an additional effect of simvastatin in reducing neuropathy; however, the mechanism underlying this effect remains unclear. We investigated the novel effects of statins on chemotherapy-induced peripheral neuropathy in mice. Mice treated with oxaliplatin or paclitaxel did not show exacerbation or improvement in cold sensations upon acetone testing with statin administration. However, concurrent oral statin treatment mitigated the nociceptive response to mechanical stimuli induced by each anti-tumor agent. Co-administration of a glutathione S-transferase inhibitor, which modulates redox reactions, abolished the ameliorative effect of statins on mechanical nociceptive behavior. Additionally, the glutathione S-transferase inhibitor did not affect normal sensory perception or impair the anti-tumor effect of chemotherapy agents. A search for GST-associated molecules and pathways using artificial intelligence revealed that GST regulates inflammatory cytokines as a regulatory or causative gene. Our findings suggest that statins have class effects that ameliorate cytotoxic anti-cancer drug-induced mechanical allodynia via GST pathway activation.

Schwann cell transient receptor potential ankyrin 1 (TRPA1) ortholog in zebrafish larvae mediates chemotherapy-induced peripheral neuropathy.

BACKGROUND AND PURPOSE: The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae. EXPERIMENTAL APPROACH: We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model. KEY RESULTS: We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1+-Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours. CONCLUSION AND IMPLICATIONS: These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom.

Oxaliplatin-induced peripheral neuropathy with hepatic arterial versus intravenous infusion in metastatic colorectal cancer.

BACKGROUND: Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far. METHODS: We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety. RESULTS: A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23). CONCLUSION: The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN.

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.

Dorsal root ganglion inflammation by oxaliplatin toxicity: DPEP1 as possible target for peripheral neuropathy prevention.

BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

Oxaliplatin-Induced Immune Thrombocytopenia in a Patient with Pancreatic Cancer.

Oxaliplatin-induced immune thrombocytopenia is a rare but potentially serious complication of chemotherapy. We present the case of a 55-year-old man with stage 4 pancreatic carcinoma who developed immune thrombocytopenia during the 18th cycle of folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy, immediately after oxaliplatin infusion. Despite treatment with methylprednisolone and platelet infusion, the patient's platelet count remained low. Subsequent plasmapheresis and continued steroid therapy resulted in a gradual improvement in platelet count and resolution of symptoms. This case highlights the importance of considering immune thrombocytopenia in patients receiving oxaliplatin-based chemotherapy, and the potential role of plasmapheresis in refractory cases. Further research is needed to elucidate the optimal management of this rare complication. LEARNING POINTS: Oxaliplatin-induced immune thrombocytopenia is a rare but potentially life-threatening side effect of chemotherapy.Management of drug-induced immune thrombocytopenia involves discontinuation of the offending drug and the use of steroids.Monitoring and follow-up are crucial in patients receiving oxaliplatin-based chemotherapy to promptly detect and manage potential hematologic emergencies, including immune thrombocytopenia.

What is the Reason That the Pharmacological Future of Chemotherapeutics in the Treatment of Lung Cancer Could Be Most Closely Related to Nanostructures? Platinum Drugs in Therapy of Non-Small and Small Cell Lung Cancer and Their Unexpected, Possible Interactions. The Review.

Over the course of several decades, anticancer treatment with chemotherapy drugs for lung cancer has not changed significantly. Unfortunately, this treatment prolongs the patient's life only by a few months, causing many side effects in the human body. It has also been proven that drugs such as Cisplatin, Carboplatin, Oxaliplatin and others can react with other substances containing an aromatic ring in which the nitrogen atom has a free electron group in its structure. Thus, such structures may have a competitive effect on the nucleobases of DNA. Therefore, scientists are looking not only for new drugs, but also for new alternative ways of delivering the drug to the cancer site. Nanotechnology seems to be a great hope in this matter. Creating a new nanomedicine would reduce the dose of the drug to an absolute minimum, and thus limit the toxic effect of the drug; it would allow for the exclusion of interactions with competitive compounds with a structure similar to nucleobases; it would also permit using the so-called targeted treatment and bypassing healthy cells; it would allow for the introduction of other treatment options, such as radiotherapy directly to the cancer site; and it would provide diagnostic possibilities. This article is a review that aims to systematize the knowledge regarding the anticancer treatment of lung cancer, but not only. It shows the clear possibility of interactions of chemotherapeutics with compounds competitive to the nitrogenous bases of DNA. It also shows the possibilities of using nanostructures as potential Platinum drug carriers, and proves that nanomedicine can easily become a new medicinal product in personalized medicine.

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.

A phase II study of FOLFOX combined with nab-paclitaxel in the treatment of metastatic or advanced unresectable gastric, gastroesophageal junction adenocarcinoma: a Big Ten Cancer Research Consortium trial.

BACKGROUND: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability. PATIENTS AND METHODS: Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate. RESULTS: The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each). CONCLUSIONS: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

Changes in AmotL2 Expression in Cells of the Human Enteral Nervous System in Oxaliplatin-Induced Enteric Neuropathy.

Gastrointestinal (GI) toxicity is a common side effect in patients undergoing oxaliplatin (OxPt)-based chemotherapy for colorectal cancer (CRC). Frequently, this complication persists in the long term and could affect the efficacy of the treatment and the patient's life quality. This long-term GI toxicity is thought to be related to OxPt-induced enteral neuropathy. AmotL2 is a member of the Angiomotin family of proteins, which play a role in cell survival, neurite outgrowth, synaptic maturation, oxidative stress protection, and inflammation. In order to assess the role of AmotL2 in OxPt-induced enteral neuropathy, we studied the expression of AmotL2 in cells of the enteric nervous system (ENS) of untreated and OxPt-treated CRC patients and its relationship with inflammation, using immunofluorescence confocal microscopy. Our results in human samples show that the total number of neurons and glial cells decreased in OxPt-treated patients, and TNF-α and AmotL2 expression was increased and colocalized in both neurons and glia. AmotL2 differential expression between OxPt-treated and untreated CRC patients shows the involvement of this scaffold protein in the inflammatory component and toxicity by OxPt in the ENS.

Misdiagnosis of severe and atypical oxaliplatin­related hypersensitivity reaction following chemotherapy combined with PD­1 inhibitor: A case report and literature review.

Although the efficacy of treatment strategies for cancer have been improving steadily over the past decade, the adverse event profile following such treatments has also become increasingly complex. The present report described the case of a 67-year-old male patient with gastric stump carcinoma with liver invasion. The patient was treated with oxaliplatin and capecitabine (CAPEOX regimen) chemotherapy, combined with the programmed cell death protein-1 (PD-1) inhibitor tislelizumab. Following treatment, the patient suffered from chills, high fever and facial flushing, followed by shock. Relevant examination results revealed severe multiple organ damage, as well as a significant elevation in IL-6 and procalcitonin (PCT) levels. Initially, the patient was diagnosed with either immune-related adverse events (irAEs) associated with cytokine release syndrome caused by tislelizumab or severe bacterial infection. However, when tislelizumab treatment was stopped and the CAPEOX chemotherapy regimen was reapplied, similar symptoms recurred. Following screening, it was finally determined that severe hypersensitivity reaction (HSR) caused by oxaliplatin was the cause underlying these symptoms. A literature review was then performed, which found that severe oxaliplatin-related HSR is rare, rendering the present case atypical. The present case exhibited no common HSR symptoms, such as cutaneous and respiratory symptoms. However, the patient suffered from serious multiple organ damage, which was misdiagnosed as irAE when oxaliplatin chemotherapy combined with the PD-1 inhibitor was administered. In addition, this apparent severe oxaliplatin-related HSR caused a significant increase in PCT levels, which was misdiagnosed as severe bacterial infection and prevented the use of glucocorticoids. This, in turn, aggravated the damage in this patient.

Oxaliplatin-associated shock in stage III colorectal cancer patients: real-world evidence in Taiwan.

Background: Oxaliplatin-associated shock (referred to as shock) is a rare but life-threatening adverse event. Objectives: This pioneering cohort study aimed to quantitatively investigate the association between oxaliplatin use and shock in patients with stage III colorectal cancer (CRC), identify potential independent risk factors for shock, and assess the cycle-to-shock during oxaliplatin treatment. Design: The study utilized a nested case-control (NCC) design to assess the association between oxaliplatin and shock and employed a case-crossover approach to address unmeasured confounders. Methods: All newly diagnosed stage III CRC patients were identified from the CRC Health Database (2012-2016). Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for oxaliplatin's link to shock incidence. Results: Among 6932 oxaliplatin recipients, 331 suffered shock. In all, 3309 controls were selected via risk-set sampling for the shock cases. Oxaliplatin use is associated with a doubled risk of shock (adjusted OR: 2.08, 95% CI: 1.23-3.52). Two independent risk factors were male sex (adjusted OR: 1.33, 95% CI: 1.05-1.69) and heart diseases (adjusted OR: 1.65, 95% CI: 1.17-2.32). The case-crossover analysis revealed a more than fourfold risk (OR: 4.4, 95% CI: 1.67-11.62). In total, 22 of 331 shock cases were exposed to oxaliplatin within 2 days of shock onset, with a median cycle-to-shock time at the seventh cycle. Conclusion: Oxaliplatin use significantly increased shock risk in stage III CRC patients. Male sex and heart disease are two independent risk factors.

This pioneering study identified potential independent risk factors and the cycle-to-shock of oxaliplatin-associated shock which is a rare but life-threatening adverse event Why was the study done? Oxaliplatin-induced anaphylactic shock (referred to as shock) is a rare but life-threatening adverse event which is a harmful and undesirable experience associated with medical care in a patient. What did the researchers do? This pioneering cohort study aimed to quantitatively investigate the association between oxaliplatin use and shock in patients with stage III colorectal cancer (CRC), identify potential independent risk factors for shock and assess the cycle-to-shock during oxaliplatin treatment. All newly diagnosed stage III CRC patients were identified from the CRC Health Database (2012­2016). The study utilized a nested case-control (NCC) design to assess the association between oxaliplatin and shock and employed a case-crossover approach to address unmeasured confounders. Conditional logistic regression was used to quantify the association between oxaliplatin and shock incidence. What did the researchers find? Among 6,932 oxaliplatin recipients, 331 suffered shock. 3,309 controls were selected via risk-set sampling for the shock cases. Oxaliplatin use is associated with a doubled risk of shock. Independent risk factors were male sex and heart diseases. The risk of shock was 33% higher for males and 65% higher for people with heart diseases compared to females and those without heart diseases. The case-crossover analysis revealed a more than four-fold risk of shock of oxaliplatin. Twenty-two of 331 shock cases were exposed to oxaliplatin within two days before the shock onset. The median cycle-to-shock time is at the seventh cycle. What do the findings mean? Oxaliplatin use significantly increased shock risk in stage III CRC patients. Male sex and having heart diseases are two independent risk factors.