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Journal of AOAC International Jun 2024The formation of charge transfer complexes (CTCs) of iodine with five chemotherapeutic drugs used for the treatment of different types of cancer has not been...
BACKGROUND
The formation of charge transfer complexes (CTCs) of iodine with five chemotherapeutic drugs used for the treatment of different types of cancer has not been investigated. These drugs were olaparib, seliciclib, vandetanib, dasatinib, and tozasertib. Additionally, these drugs need an appropriate general spectrophotometric assay for their analysis in the dosage forms regardless of the differences in their chemical structures.
OBJECTIVE
The aim of this study was the development of a novel microwell spectrophotometric assay (MW-SPA) for one-step determination of these drugs via their intereactions with iodine resulted in instantaneous producing a bright lemon yellow-colored CTCs.
METHODS
The spectrophotometric study of the CTCs were conducted, and all CTCs were characterized. Site(s) of interaction on each drug were assigned, and the MW-SPA was developed and applied to the analysis of dosage forms.
RESULTS
The findings confirmed that the reactions proceeded via CTCs formation. Beer's law was obeyed over a general concentration range of 1-6 µg/mL. The limits of detection and quantitation were in the ranges of 0.5-2.1 and 1.5-6.4 µg/mL, respectively. The proposed MW-SPA demonstrated excellent precisions as the relative standard deviations were < 2.24 and 2.23% for the intra- and inter-assay precision, respectively. Recovery studies demonstrated the accuracy of MW-SPA. Successful determination of all drugs in bulk and tablet forms was achieved using the MW-SPA. The environmental sustainability of the proposed methodology was determined, providing evidence of the assay's alignment with the basis of green analytical chemistry. The high throughput of the assay was documented.
CONCLUSIONS
In contrast to other existing methods, the MW-SPA described herein valid for analyzing all drugs at the same wavelength.
HIGHLIGHTS
The assay is useful for routine analysis of drugs in their formulations in quality control laboratories.
PubMed: 38941505
DOI: 10.1093/jaoacint/qsae052 -
Investigational New Drugs Jun 2024The present study aimed to clarify the hypothesis that auger emitter I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression...
The present study aimed to clarify the hypothesis that auger emitter I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of I and Olaparib on pancreatic cancer progression. In summary, I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer.
PubMed: 38941055
DOI: 10.1007/s10637-024-01454-y -
Molecular Biology Reports Jun 2024The mutational status of ovarian cancer cell line IGROV-1 is inconsistent across the literature, suggestive of multiple clonal populations of the cell line. IGROV-1 has...
BACKGROUND
The mutational status of ovarian cancer cell line IGROV-1 is inconsistent across the literature, suggestive of multiple clonal populations of the cell line. IGROV-1 has previously been categorised as an inappropriate model for high-grade serous ovarian cancer.
METHODS
IGROV-1 cells were obtained from the Netherlands Cancer Institute (IGROV-1-NKI) and the MD Anderson Cancer Centre (IGROV-1-MDA). Cell lines were STR fingerprinted and had their chromosomal copy number analysed and BRCA1/2 genes sequenced. Mutation status of ovarian cancer-related genes were extracted from the literature.
RESULTS
The IGROV-1-NKI cell line has a tetraploid chromosomal profile. In contrast, the IGROV-1-MDA cell line has pseudo-normal chromosomes. The IGROV-1-NKI and IGROV-MDA are both STR matches (80.7% and 84.6%) to the original IGROV-1 cells isolated in 1985. However, IGROV-1-NKI and IGROV-1-MDA are not an STR match to each other (78.1%) indicating genetic drift. The BRCA1 and BRCA2 gene sequences are 100% identical between IGROV-1-MDA and IGROV-1-NKI, including a BRCA1 heterozygous deleterious mutation. The IGROV-1-MDA cells are more resistant to cisplatin and olaparib than IGROV-1-NKI. IGROV-1 has a mutational profile consistent with both Type I (PTEN, PIK3CA and ARID1A) and Type II ovarian cancer (BRCA1, TP53) and is likely to be a Type II high-grade serous carcinoma of the SET (Solid, pseudo-Endometroid and Transitional cell carcinoma-like morphology) subtype.
CONCLUSIONS
Routine testing of chromosomal copy number as well as the mutational status of ovarian cancer related genes should become the new standard alongside STR fingerprinting to ensure that ovarian cancer cell lines are appropriate models.
Topics: Female; Ovarian Neoplasms; Humans; Cell Line, Tumor; Mutation; DNA Copy Number Variations; BRCA1 Protein; BRCA2 Protein; Gene Dosage
PubMed: 38940864
DOI: 10.1007/s11033-024-09747-4 -
Biomedicines Jun 2024PARP inhibitors are used to treat cancers with a deficient homologous recombination (HR) DNA repair pathway. Interestingly, recent studies revealed that HR repair could...
PARP inhibitors are used to treat cancers with a deficient homologous recombination (HR) DNA repair pathway. Interestingly, recent studies revealed that HR repair could be pharmacologically impaired by the inhibition of histone lysine demethylases (KDM). Thus, we investigated whether KDM inhibitors could sensitize head and neck cancer cells, which are usually HR proficient, to PARP inhibition or cisplatin. Therefore, we explored the effects of double combinations of KDM4-6 inhibitors (ML324, CPI-455, GSK-J4, and JIB-04) with olaparib or cisplatin, or their triple combinations with both drugs, on the level of DNA damage and apoptosis. FaDu and SCC-040 cells were treated with individual compounds and their combinations, and cell viability, apoptosis, DNA damage, and gene expression were assessed using the resazurin assay, Annexin V staining, H2A.X activation, and qPCR, respectively. Combinations of KDM inhibitors with cisplatin enhanced cytotoxic effects, unlike combinations with olaparib. Triple combinations of KDM inhibitors with cisplatin and olaparib exhibited the best cytotoxic activity, which was associated with DNA damage accumulation and altered expression of genes associated with apoptosis induction and cell cycle arrest. In conclusion, triple combinations of KDM inhibitors (especially GSK-J4 and JIB-04) with cisplatin and olaparib represent a promising strategy for head and neck cancer treatment.
PubMed: 38927566
DOI: 10.3390/biomedicines12061359 -
Biomolecules May 2024BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with...
BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that a BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitors sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin, and paclitaxel synergistically (combination index; CI < 1). BAY1816032 significantly increased the radiation sensitization of SUM159 and MDA-MB-231 by olaparib, cisplatin, or paclitaxel at non-toxic concentrations (doses well below the IC concentrations). Importantly, the small molecular inhibitor of BUB1 synergistically (CI < 1) sensitized the BRCA mutant TNBC cell line HCC1937 to olaparib. Furthermore, the BUB1 inhibitor significantly increased the radiation enhancement ratio (rER) in HCC1937 cells (rER 1.34) compared to either agent alone (BUB1i rER 1.19; PARPi rER 1.04). The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Line, Tumor; Phthalazines; Cisplatin; Piperazines; Paclitaxel; Protein Serine-Threonine Kinases; Female; Antineoplastic Agents; Cell Proliferation; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; BRCA1 Protein
PubMed: 38927028
DOI: 10.3390/biom14060625 -
Nucleic Acids Research Jun 2024Replication repriming by the specialized primase-polymerase PRIMPOL ensures the continuity of DNA synthesis during replication stress. PRIMPOL activity generates...
Replication repriming by the specialized primase-polymerase PRIMPOL ensures the continuity of DNA synthesis during replication stress. PRIMPOL activity generates residual post-replicative single-stranded nascent DNA gaps, which are linked with mutagenesis and chemosensitivity in BRCA1/2-deficient models, and which are suppressed by replication fork reversal mediated by the DNA translocases SMARCAL1 and ZRANB3. Here, we report that the MRE11 regulator MRNIP limits the prevalence of PRIMPOL and MRE11-dependent ssDNA gaps in cells in which fork reversal is perturbed either by treatment with the PARP inhibitor Olaparib, or by depletion of SMARCAL1 or ZRANB3. MRNIP-deficient cells are sensitive to PARP inhibition and accumulate PRIMPOL-dependent DNA damage, supportive of a pro-survival role for MRNIP linked to the regulation of gap prevalence. In MRNIP-deficient cells, post-replicative gap filling is driven in S-phase by UBC13-mediated template switching involving REV1 and the TLS polymerase Pol-ζ. Our findings represent the first report of modulation of post-replicative ssDNA gap dynamics by a direct MRE11 regulator.
PubMed: 38917325
DOI: 10.1093/nar/gkae546 -
Current Treatment Options in Oncology Jun 2024The management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape... (Review)
Review
The management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer. The implementation of various therapeutic agents has improved overall survival but despite the promising advances in therapeutic options, mCRPC remains incurable. The focus of treatment should be not only to improve survival but also to preserve the patient's quality of life (QoL) and ameliorate cancer-related symptoms such as pain. The choice and sequence of therapy for mCRPC patients are complex and influenced by various factors, such as side effects, disease burden, treatment history, comorbidities, patient preference and, more recently, the presence of actionable genomic alterations or biomarkers. Docetaxel is the first-line treatment for chemo-naïve patients with good performance status and those who have yet to progress on docetaxel in the castration-sensitive setting. Novel androgen agents (NHAs), such as abiraterone and enzalutamide, are effective treatment options that are utilized as second-line options. These medications can be considered upfront in frail patients or patients who are NHA naïve. Current guidelines recommend genetic testing in mCRPC for mutations in DNA repair deficiency genes to inform treatment decisions, as for example in breast cancer gene mutation testing. Other potential biomarkers being investigated include phosphatase and tensin homologues and homologous recombination repair genes. Despite a growing number of studies incorporating biomarkers in their trial designs, to date, only olaparib in the PROFOUND study and lutetium-177 in the VISION trial have improved survival. This is an unmet need, and future trials should focus on biomarker-guided treatment strategies. The advent of novel noncytotoxic agents has enhanced targeted drug delivery and improved treatment responses with favourable toxicity profiling. Trials should continue to incorporate and report health-related QoL scores and functional assessments into their trial designs.
PubMed: 38913213
DOI: 10.1007/s11864-024-01215-2 -
Cureus May 2024Triple-negative breast cancer poses distinct challenges because it lacks hormone receptors and does not have human epidermal growth factor receptor 2 (HER2)...
Triple-negative breast cancer poses distinct challenges because it lacks hormone receptors and does not have human epidermal growth factor receptor 2 (HER2) amplification. Mutations in BRCA1/2 genes are associated with homologous recombination deficiency tumors, rendering them susceptible to poly (ADP-ribose) polymerase (PARP) inhibitors. Notably, germline BRCA1/2 mutations are linked to distinct clinical features, including an increased risk of triple-negative breast cancer (TNBC) and a younger age of onset. PARP inhibitors such as olaparib and talazoparib have demonstrated efficacy in patients with BRCA mutations, leading to FDA approvals for ovarian and breast cancers. However, there remains limited data on PARP inhibitor response rates in patients with somatic BRCA mutations. This case series demonstrates the use of rucaparib in metastatic breast cancer patients harboring both germline and somatic BRCA1/2 mutations, discussing the advancing landscape of targeted therapies in breast cancer management. In the first case, despite undergoing anthracycline-based chemotherapy followed by hormonal therapy, disease progression ensued. However, transitioning to rucaparib yielded a remarkable complete response lasting over two years, highlighting its efficacy in this clinical setting. Similarly, in the second case, rucaparib demonstrated effectiveness as a maintenance therapy subsequent to achieving a near-complete response to taxane and platinum-based treatment. These findings emphasize the promising role of rucaparib in managing metastatic breast cancer in patients with BRCA1/2 mutations, further contributing to the expanding armamentarium of targeted therapies in breast cancer care.
PubMed: 38910707
DOI: 10.7759/cureus.60963 -
International Journal of Gynecological... Jun 2024Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
BACKGROUND
Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
OBJECTIVE
To compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and patient decision-making.
METHODS
The PubMed, Embase, Cochrane, and Web of Science Databases were reviewed from January 1, 2010 to October 30, 2023, for phase III randomized controlled trials of first-line immunotherapy combinations in patients with advanced endometrial cancer. Bayesian network meta-analysis was performed to obtain hazard ratios (HRs) of overall survival and progression-free survival, relative risks (RRs) of adverse events, and corresponding p value. The lifetime Markov model of cost-effectiveness analysis was developed to summarize the cost, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios at the US$150 000/QALY of willingness-to-pay of six first-line treatment strategies.
RESULTS
Four trials were identified, involving 2577 patients. Dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. Further, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population.
CONCLUSION
First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.
PubMed: 38901970
DOI: 10.1136/ijgc-2024-005296 -
Environmental Toxicology Jun 2024Despite recent advances in treatment, non-small cell lung cancer (NSCLC) continues to have a high mortality rate. Currently, NSCLC pathogenesis requires further...
Despite recent advances in treatment, non-small cell lung cancer (NSCLC) continues to have a high mortality rate. Currently, NSCLC pathogenesis requires further investigation, and therapeutic drugs are still under development. Homologous recombination repair (HRR) repairs severe DNA double-strand breaks. Homologous recombination repair deficiency (HRD) occurs when HRR is impaired and causes irreparable double-strand DNA damage, leading to genomic instability and increasing the risk of cancer development. Poly(ADP-ribose) polymerase (PARP) inhibitors can effectively treat HRD-positive tumors. Extracellular heat shock protein 90α (eHSP90α) is highly expressed in hypoxic environments and inhibits apoptosis, thereby increasing cellular tolerance. Here, we investigated the relationship between eHSP90α and HRR in NSCLC. DNA damage models were established in NSCLC cell lines (A549 and H1299). The activation of DNA damage and HRR markers, apoptosis, proliferation, and migration were investigated. In vivo tumor models were established using BALB/c nude mice and A549 cells. We found that human recombinant HSP90α stimulation further activated HRR and reduced DNA damage extent; however, eHSP90α monoclonal antibody, 1G6-D7, effectively inhibited HRR. HRR inhibition and increased apoptosis were observed after LRP1 knockdown; this effect could not be reversed with hrHSP90α addition. The combined use of 1G6-D7 and olaparib caused significant apoptosis and HRR inhibition in vitro and demonstrated promising anti-tumor effects in vivo. Extracellular HSP90α may be involved in HRR in NSCLC through LRP1. The combined use of 1G6-D7 and PARP inhibitors may exert anti-tumor effects by inhibiting DNA repair and further inducing apoptosis of NSCLC cells.
PubMed: 38899512
DOI: 10.1002/tox.24356