Vinca Alkaloids Research Articles

The Application of Kinesin Inhibitors in Medical Issues.

Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.

Antiproliferative Activity of Cephalotaxus Esters: Overcoming Chemoresistance.

Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1). In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells. Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via caspase 3 cleavage, leading to apoptosis. Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

HURP binding to the vinca domain of β-tubulin accounts for cancer drug resistance

Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells’ sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP’s tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain’s role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment.

Green Poison : A Sustainable Approach to Use Plant Toxin as an Anticancer Agent

The rising interest in plant-derived phytochemicals as cancer therapies has revealed numerous bio-active compounds with potent therapeutic potential. Compounds like vinca alkaloids, taxane , and berberine exhibit diverse biological activities, including anti-tumor, proving effective against various cancer types. Despite the toxicity of some medicinal plants, this feature can be harnessed for drug discovery, offering new treatments for cancer. Plant metabolites target tumor growth by inhibiting tumor-promoting enzymes, repairing DNA, and boosting immune responses. Compounds like vinblastine disrupt micro-tubule dynamics, while curcumin inhibits cancer cell proliferation. Toxic plant-derived metabolites, such as podophyllotoxin and camptothecin, demonstrate unique cancer-fighting mechanisms by targeting topoisomerases and inducing apoptosis. Integrating these phytochemical promise for advancing cancer prevention and treatment, offering more sustainable and effective options.

A real-world pharmacovigilance study using disproportionality analysis of United States Food and Drug Administration Adverse Event Reporting System events for vinca alkaloids: comparing vinorelbine and Vincristine

ABSTRACT Background Vinca alkaloids are widely used in cancer treatment for their ability to target microtubule dynamics. While their efficacy in treating certain cancers is well-established, the full spectrum of their adverse event profiles remains an area of ongoing research. Methods We analyzed AEs related to vinorelbine and vincristine using a retrospective case/non-case approach with data from the FDA Adverse Event Reporting System (FAERS). We applied various algorithms to detect AE signals: the reporting odds ratio (ROR) and proportional reporting ratio (PRR) measured disproportionality and association strength; the Bayesian confidence propagation neural network (BCPNN) calculated the Information Component (IC) for associations against background rates; and the multi-item gamma Poisson shrinker (MGPS) yielded empirical Bayes geometric mean (EBGM) values, accounting for reporting variability. Results Both medications significantly involve the blood and lymphatic systems, with vinorelbine reporting 401 cases in this System Organ Class (SOC), exhibiting a ROR of 17.4, PRR of 12.4, IC of 3.63, and EBGM of 12.38. An intersection analysis of Preferred Terms (PTs) has uncovered previously unreported AEs shared by both drugs, including posterior reversible encephalopathy syndrome and inappropriate antidiuretic hormone secretion. Conclusions This analysis highlights the need for ongoing research of the risks associated with vinorelbine and vincristine.

Associations between acupuncture and uses of opioids and neuropsychiatric medication following chemotherapy-induced peripheral neuropathy among patients with breast cancer.

216 Background: Chemotherapy-induced peripheral neuropathy (CIPN) features debilitative neuropathic pain and neurologic deficits, commonly present in breast cancer population exposed to certain chemo-agents. Given suboptimal effects often rendered by limited therapeutic options, CIPN is associated to psychological distress and drug-seeking behaviors, which leads to heightened functional impairment and disease burden. Acupuncture has gained clinical recognitions for alleviating pain and mental distress, but its impact on medication uses for pain or psychiatric disorders in CIPN remains unclear. As such, this study aims to investigate the association between acupuncture and use of these medications among breast cancer patients experiencing CIPN. Methods: This survival analysis utilized data from the TriNetX Network comprising real-time electronic health records from over 60 healthcare organizations across the United States. Breast cancer patients over 18 at the index date within 01/01/1997 (inception of acupuncture practice in US) and 05/10/2023, diagnosed with CIPN after exposure to chemo-agents such as taxane, platinum, vinca alkaloids, thalidomide, or bortezomib, were identified as the baseline cohort. Patients who received at least three acupuncture sessions post CIPN diagnosis were compared to those without any acupuncture record. Endpoints included prescription of sedative/hypnotics, anti-depressants, anti-psychotics, anti-convulsant agents, and opioid analgesics, within a twelve-month follow-up period after index date. Antibiotics use was the negative control outcome. A 1:1 propensity-score-matching (PSM) method was applied for between-group balance of demographics, BMI, cancer treatment history, health comorbidities, and concurrent medications, followed by hazard ratios and 95% CI calculation using Cox regression model. Results: Among 398 PSM pairs, acupuncture group demonstrated significantly lower hazards of sedative/hypnotics (HR= 0.74, 95% CI 0.61-0.9), anti-depressants (HR= 0.75, 95% CI 0.61-0.93), anti-psychotics (HR= 0.74, 95% CI 0.58-0.96), anticonvulsants (HR= 0.48, 95% CI 0.27-0.87), and opioids (HR= 0.78, 95% CI 0.65-0.94) use, whereas antibiotics showed insignificant result (HR= 0.75, 95% CI 0.55-1.02). The significance sustained after sensitivity analyses, excluding patients with concurrent other cancers, and narrowing follow-up period down to the last nine months to concentrate on treatment effects. Conclusions: Our study suggests a decreased need of opioids and neuropsychiatric medication associated with acupuncture treatment among breast cancer patients endorsing CIPN. Rigorous clinical studies are warranted to validate the causal underpinnings.

Characterization of Non-Small Cell Lung Cancer Tissue by Quantitative Assessment of Class III β-Tubulin Expression

Background. The cytoskeletal protein β-tubulin class III (Tubb3) is associated with tumor resistance to taxanes and vinca alkaloids, as well as with the metastatic potential of neoplasm, however, data from immunohistochemical analysis of Tubb3 expression in non-small cell lung cancer (NSCLC) tissue are few and contradictory. Purpose. Characterization of the level and intensity of Tubb3 expression in NSCLC tissue and analysis of the identified parameters correlation with clinically significant characteristics of the disease. Methods. Quantitative assessment of the level and intensity of Tubb3 expression in 120 surgical samples of NSCLC was carried out by immunofluorescence method associated with flow cytometry. Primary rabbit monoclonal antibodies specific to Tubb3 and secondary anti-rabbit antibodies conjugated with fluorescent dye DyLight650 (ab98510, UK) were used. The expression of the marker was assessed by two parameters: the level of expression measured as the percentage of the cells expressing Tubb3 and the intensity of expression in conventional units (CU) represented as the ratio of the geometric mean fluorescence intensity in the experimental and control samples (cells incubated with secondary antibodies only). Results. 1. Tubb3 expression was detected in all NSCLC samples studied. The median level and intensity of Tubb3 expression was 30.5% and 2.0 CU with significant differences (up to 10 times) in the quantitative values of both parameters in different patients. 2. The distribution of the studied tumors in terms of the level and intensity of Tubb3 expression differs from normal (P<0.001), the associative relationship between the assessed parameters is very strong (Spearman's rank correlation coefficient was 0.91; P<0.0001). 3. Statistical analysis did not reveal correlations between the level of Tubb3 expression and the gender and smoking status of the patients, with the degree of tumor differentiation, as well as with the stage of NSCLC. 4. In the group of lung adenocarcinomas, the median level of Tubb3 expression is higher compared with squamous cell lung cancer in male and female patients (P=0.01). Conclusion. High heterogeneity of Tubb3 expression level in NSCLC tissue in the patients and differences in the parameters between the tumors of various histotypes indicate the importance of further correlation analysis of Tubb3 expression level with the patients' life span in order to identify the prognostic value of the marker.

Protocol-Stipulated Dose Modification to Manage Chemotherapy-Induced Peripheral Neuropathy in Children, Adolescents, and Young Adults With High-Risk Hodgkin Lymphoma.

Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for classic Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children's Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) with bleomycin containing doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC; standard arm) in patients with high-risk cHL ages 2-21 years. AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by the presence of dose modification. Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 v 19.8%, P = .91). CIPN dose modifications occurred more frequently in the BV arm (9.5% v 2.8%, P = .001); however, most patients with CIPN on the BV arm received full-dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, although older age was significantly associated with the risk of VCR dose modifications for CIPN. A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331 minimized the effect of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV arm.

The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment.

The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer.

The evolution and history of Vinca alkaloids: From the Big Bang to the treatment of pediatric acute leukemia.

An attractive flower from the island of Madagascar has in part saved the lives of thousands of children with acute lymphoblastic leukemia (ALL). Random mutations and alterations to the genome led to the evolution of genes encoding enzymes, which would provide the periwinkle flower an arsenal of secondary metabolites to survive within the Madagascar ecosystem. Of the over 200 alkaloid compounds synthesized by the periwinkle, vincristine and vinblastine are the two most well-known being used for chemotherapy treatments, including for children with ALL. The complexities of the multi-step biosynthesis of vincristine and vinblastine, which has taken years to decode, highlight the importance of protecting the vast biodiversity on earth as other natural products that can save lives await to be discovered. This review addresses the discovery of vincristine and vinblastine, as well as the history of their existence, in nature.

Drug fever-an immune-mediated delayed type hypersensitivity reaction to Vinca alkaloids in pediatric oncology patients, possibly mediated by cysteinyl leukotrienes.

Drug hypersensitivity reactions are common in pediatric hemato-oncology patients due to multiple factors including immune compromise and pharmacological complexities. Fever can signify severe delayed-type hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The etiology of fever as an isolated hypersensitivity reaction to chemotherapeutic agents not fully understood. Here, we report three children with intracranial neoplasms experiencing recurrent febrile reactions following Vinca alkaloid-based chemotherapy, mitigated by cysteinyl leukotriene receptor antagonist therapy. We present a series of pediatric patients with diverse intracranial neoplasms who developed recurrent fever episodes after multiple courses of Vinca alkaloid-based chemotherapy. Treatment involved prophylactic and post-chemotherapy administration of a cysteinyl leukotriene receptor antagonist to prevent fever episodes and enable completion of chemotherapy regimens without protocol modifications or desensitization. All three patients experienced fever consistent with delayed-type hypersensitivity reactions to Vinca alkaloids. Prophylactic use of the leukotriene antagonist Montelukast successfully prevented fever recurrence, allowing uninterrupted completion of chemotherapy courses. Our findings suggest that Montelukast, a leukotriene antagonist, may be beneficial in managing fever as a delayed-type hypersensitivity reaction to Vinca alkaloids in pediatric patients. Further research is warranted to elucidate the underlying mechanisms and leukotriene pathways involved in drug-induced fever reactions.

Oral Neuropathy Associated with Commonly used Chemotherapeutic Agents: A Narrative Review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of cytotoxic chemotherapeutic agents; its incidence largely varies, depending on type, dose, agent and preexisting risk factors. Oral-and-perioral-CIPN (OCIPN) is underreported. Neurotoxic agents can cause jaw pain or numbness. This review aims to present available data on OCIPN RECENT FINDINGS: A narrative literature review, following SANRA guidelines was conducted. PubMed and Cochrane databases were searched until September 2023. Articles referring to neuropathy or neuropathic pain due to head and neck cancer, head and neck radiotherapy, oropharyngeal mucositis, infection or post-surgical pain were excluded. Platinum-based chemotherapeutics, taxanes, vinca alkaloids, immunomodulatory and alkylating agents can cause OCIPN. Platinum-based chemotherapeutics can cause orofacial cold sensitivity, orofacial and jaw pain, oral cavity tingling and teeth hypersensitivity. Taxanes may induce oral cavity and tongue numbness and tingling as well as hot hypersensitivity. Vinca alkaloids may cause jaw, teeth and lips pain and oral mucosa hyperalgesia. Immunomodulatory drugs can cause lips, tongue and perioral numbness, while alkylating agents induce tongue and lips tingling and teeth cold-hypersensitivity. Chemotherapy may cause OCIPN due to changes in cellular structure and function, like alterations in membrane receptors and neurotransmission. OCIPN should be documented and physicians, dentists and health care providers should be alerted.

Novel Piperazine Derivatives of Vindoline as Anticancer Agents.

A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.

Preventive Effect of Neuromuscular Training on Chemotherapy-Induced Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and clinically relevant adverse effect of chemotherapy, negatively impacting patient quality of life. The lack of effective preventive or therapeutic options regarding CIPN often requires changes in cancer therapy, potentially resulting in reduced survival. To determine whether sensorimotor training (SMT) and whole-body vibration (WBV) training reduce symptoms and decrease the onset of CIPN. This prospective multicenter randomized clinical trial (STOP) followed up patients over 5 years at 4 centers in or near Cologne, Germany. Patients undergoing treatment with oxaliplatin or vinca alkaloids were recruited. Participants were recruited from May 2014 to November 2020. Data were last analyzed in June 2021. Participants in the intervention groups performed supervised SMT or WBV training sessions twice a week, each lasting approximately 15 to 30 minutes, concomitant to medical therapy. The primary end point was the incidence of CIPN. Secondary end points included subjective neuropathy symptoms, balance control, physical activity levels, quality of life, and clinical outcome. For cross-stratum evaluations, the Mantel-Haenszel test (MH) was used, and within individual strata, Fisher exact test was used for analysis. A total of 1605 patients were screened, and 1196 patients did not meet all inclusion criteria, with 251 further excluded or declining participation. A total of 158 patients (mean [SD] age, 49.1 [18.0-82.0] years; 93 [58.9%] male) were randomized into 1 of 3 groups: 55 (34.8%) in SMT, 53 (33.5%) in WBV, and 50 (31.6%) in treatment as usual (TAU). The incidence of CIPN in participants was significantly lower in both intervention groups compared to the control group (TAU): (SMT, 12 of 40 [30.0%; 95% CI, 17.9%-42.1%] and WBV, 14 of 34 [41.2%; 95% CI, 27.9%-54.5%] vs TAU, 24 of 34 [70.6%; 95% CI, 58.0%-83.2%]; P = .002 for intention to treat-MH). Patients receiving vinca alkaloids and performing SMT benefited the most. Results were more pronounced in a per-protocol analysis (>75% participation in the intervention) (SMT, 8 of 28 [28.6%; 95% CI, 16.6%-40.5%] and WBV, 9 of 24 [37.5%; 95% CI, 24.4%-50.5%] vs TAU, 22 of 30 [73.3%; 95% CI, 61.6%-85.6%]). Improvements in favor of SMT compared to TAU were found for balance control bipedal with eyes open; bipedal with eyes closed; monopedal, vibration sensitivity, sense of touch, lower leg strength, pain reduction, burning sensation, chemotherapy dose reductions, and mortality. This randomized clinical trial provides initial evidence that neuromuscular training decreases the onset of CIPN. German Clinical Trials Register: DRKS00006088.

Vincristine attenuates isoprenaline-induced cardiac hypertrophy in male Wistar rats via suppression of ROS/NO/NF-қB signalling pathways

Vincristine (VCR), a vinca alkaloid with anti-tumor and anti-oxidant properties, is acclaimed to possess cardioprotective action. However, the molecular mechanism underlying this protective effect remains unknown. This study investigated the effects of VCR on isoprenaline (ISO), a beta-adrenergic receptor agonist, induced cardiac hypertrophy in male Wistar rats. Animals were pre-treated with ISO (1 mg/kg) intraperitoneally for 14 days before VCR (25 μg/kg) intraperitoneal injection from days 1 to 28. Thereafter, mechanical, and electrical activities of the hearts of the rats were measured using a non-invasive blood pressure monitor and an electrocardiograph, respectively. After which, the heart was homogenized, and supernatants were assayed for contractile proteins: endothelin-1, cardiac troponin-1, angiotensin-II, and creatine kinase-MB, with markers of oxidative/nitrergic stress (SOD, CAT, MDA, GSH, and NO), inflammation (TNF-a and IL-6, NF-kB), and caspase-3 indicative of VCR reduced elevated blood pressure and reversed the abnormal electrocardiogram. ISO-induced increased endothelin-1, cardiac troponin-1, angiotensin-II, and creatine phosphokinase-MB, which were reversed by VCR. ISO also increased TNF-α, IL-6, NF-kB expression with increased caspase-3-mediated apoptosis in the heart. However, VCR reduced ISO-induced inflammation and apoptosis, with improved endogenous antioxidant agents (GSH, SOD, CAT) relative to ISO controls. Moreso, VCR, protected against ISO-induced histoarchitectural degeneration of cardiac myofibre. The result of this study revealed that VCR treatment significantly reverses ISO-induced cardiac hypertrophic phenotypes, via mechanisms connected to improved levels of proteins involved in excitation-contraction, and suppression of oxido-inflammatory and apoptotic pathways.

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity.

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.

Mechanisms of mitotic inhibition in human aorta endothelial cells: Molecular and morphological in vitro spectroscopic studies

Mitotic inhibitors are drugs commonly used in chemotherapy, but their nonspecific and indiscriminate distribution throughout the body after intravenous administration can lead to serious side effects, particularly on the cardiovascular system. In this context, our investigation into the mechanism of the cytotoxic effects on endothelial cells of mitotic inhibitors widely used in cancer treatment, such as paclitaxel (also known as Taxol) and Vinca alkaloids, holds significant practical implications. Understanding these mechanisms can lead to more targeted and less harmful cancer treatments.Human aorta endothelial cells (HAECs) were incubated with selected mitotic inhibitors in a wide range of concentrations close to those in human plasma during anticancer therapy. The analysis of single cells imaged by Raman spectroscopy allowed for visualization of the nuclear, cytoplasmic, and perinuclear areas to assess biochemical changes induced by the drug’s action. The results showed significant changes in the morphology and molecular composition of the nucleus. Moreover, an effect of a given drug on the cytoplasm was observed, which can be related to its mechanism of action (MoA). Raman data supported by fluorescence microscopy measurements identified unique changes in DNA form and proteins and revealed drug-induced inflammation of endothelial cells.The primary goal of mitotic inhibitors is based on the impairment of tubulin formation and the inhibition of the mitosis process. While all three drugs affect microtubules and disrupt cell division, they do so through different MoA, i.e., Vinca alkaloids inhibit microtubule formation, whereas paclitaxel stabilizes microtubules. To sum up, the work shows how a specific drug can interact with endothelial cells.

Catharanthine, an anticancer vinca alkaloid: an in silico and in vitro analysis of the autophagic system as the major mechanism of cell death in liver HepG2 cells.

Catharanthine, a component of the anticancer drug vinblastine along with vindoline, disrupts the cell cycle by interfering with mitotic spindle formation. Apart from their antioxidant properties, vinca alkaloids like catharanthine inhibit phosphodiesterase activity and elevate intracellular cAMP levels. The aim of this study was to investigate how catharantine affects apoptosis and autophagy.This study conducted experiments on HepG2 liver carcinoma cells with varying doses of catharanthine to evaluate cell death rates and viability and determine the IC50concentration via MTT assays. The apoptotic and autophagic effects of catharanthine were assessed using flow cytometry with annexin V and PI staining, while the expression of autophagy-related genes was analyzed through quantitative PCR. Additionally, molecular docking and molecular dynamics simulations were employed to further investigate catharanthine's impact on autophagy mechanisms.The study showed that catharanthine reduced oxidative stress and triggered apoptosis in HepG2 cells in a dose-dependent manner. Catharanthine also upregulated the expression of autophagy-related genes like LC3, Beclin1, and ULK1. Notably, catharanthine increased sirtuin-1 levels, a known autophagy inducer, while decreasing Akt expression compared to untreated cells. Molecular docking results indicated rapamycin had a stronger binding affinity with FRB (-10.7 KJ/mol-1) than catharanthine (-7.3 KJ/mol-1). Additionally, molecular dynamics simulations revealed that catharanthine interacted effectively with the FRB domain of mTOR, displaying stability and a strong binding affinity, although not as potent as rapamycin.In summary, besides its cytotoxic and pro-apoptotic effects, catharanthine activates autophagy signaling pathways and induces autophagic necrosis by inhibiting mTOR.

A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy treatment (ACT).

TPS12151 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapy among people who experience cancer, presenting pain, numbness, tingling, and motor weakness. CIPN worsens quality of life and disrupts active treatment regimens. Currently, duloxetine is the only ASCO-recommended painful CIPN treatment after chemotherapy completion. Still, it has undesirable side effects, i.e., fatigue, sleep disturbance, and digestive symptoms, posing a pressing need for well-tolerated, evidence-based interventions. Our pilot study demonstrated the feasibility and preliminary efficacy of acupuncture in relieving CIPN pain. Based on that, we developed the ACT trial to evaluate the effect of acupuncture on improving pain and other related symptoms among cancer survivors with CIPN pain. Methods: ACT is a prospective phase III multicenter, parallel two-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT04917796). ACT aims to determine the efficacy of an eight-week electroacupuncture (EA) treatment vs. sham acupuncture (SA) on improving CIPN symptoms severity in cancer survivors. We plan to enroll 250 participants to detect an effect size of at least 0.45 for the primary pain outcome at 12 weeks post-randomization between EA vs. SA, with 80% power and a 1% Type I error rate, assuming a 10% loss to follow-up. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, and 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item. We randomly allocate participants to receive ten real or sham acupuncture treatments over eight weeks at two centers and their regional clinics. Aside from patient-reported outcome measures (i.e., BPI, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, EORTC Quality of Life Questionnaire-CIPN 20), we conduct quantitative sensory testing to assess changes in sensory function. The primary study endpoint is week 12, and the secondary study endpoint is week 24. Progress: 1) We are currently transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, a total of 133 of the planned 250 participants have been enrolled; 3) The DSMB last reviewed the trial in December 2023, and suggested that the trial continue as planned at MSK. We anticipate initiating participant enrollment at DFCI in February 2024. Accrual completion is expected by December 2024. Clinical trial information: NCT04917796 .

A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment (YCT).

TPS12152 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is common and debilitating among cancer survivors receiving neurotoxic chemotherapy, which can cause functional disabilities and significantly increase the risk of falls. There are limited approaches to managing CIPN symptoms and related functional limitations. Our pilot study demonstrated yoga therapy's feasibility and preliminary efficacy in improving CIPN pain and functional outcomes. We developed the YCT trial to assess the effect of yoga therapy on improving pain and balance symptoms among cancer survivors with CIPN pain. Methods: YCT is a prospective phase III multicenter, parallel three-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT05121558). YCT aims to determine the efficacy of an eight-week yoga treatment vs. education control (EC) vs. usual care (UC) in improving CIPN pain and balance in cancer survivors. We plan to enroll and randomize 268 participants (2:1:1) to yoga, EC, and UC groups to detect an effect size of at least 0.48 for the primary pain outcome at eight weeks post-randomization between yoga vs. EC, with 80% power and a 2.5% Type I error rate, assuming 12% attrition by week 8 and 20% attrition by week 24. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item, and 4) who experience self-identified CIPN balance difficulty. Eligible subjects in the yoga arm will receive hourly gentle therapeutic yoga classes taught by protocol-trained oncology yoga instructors, twice weekly for eight weeks, and practice home-based yoga. Subjects in the EC arm will receive hourly education classes taught by protocol-trained healthcare instructors twice weekly for eight weeks. Subjects in the UC arm will continue usual care for eight weeks. We offer free yoga sessions for participants in control groups after study completion. Aside from patient-reported outcome measures (i.e., BPI, FACT/GOG-Ntx, QLQ-CIPN 20), we measured functional improvements by functional reach, timed up-and-go, and chair-to-stand tests. We also conducted quantitative sensory testing to assess changes in sensory function. Progress: 1) We are transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, 104 of the planned 268 participants have been enrolled. We anticipate initiating participant enrollment at DFCI in February 2024. Anticipated accrual completion: March 2025. Clinical trial information: NCT05121558 .