NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Chen, Thomas C.; Minea, Radu O.; Swenson, Steve; Yang, Zhuoyue; Thein, Thu Zan; Schönthal, Axel H.

doi:10.3390/cancers14246065

Cited by 5 publications

(4 citation statements)

References 64 publications

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“…In comparison, none of the corresponding 2 treatment groups of rats administered with NEO212 revealed a significant reduction in WBC count, and all rats continued to thrive. 30 When combined with radiation, NEO212 did not reveal any significant detrimental impact on the bone marrow or peripheral blood cell counts, further reinforcing our previous observations.…”

Section: Discussionsupporting

confidence: 86%

“…In a rat model, we applied greatly increased dosages of NEO212—in parallel to equal dosages of TMZ for comparison purposes—in an attempt to force the appearance of toxic signs. 30 In these experiments, 100 mg/kg TMZ administered daily over 5 days caused a significant reduction in WBC counts, and increasing the dose to 200 mg/kg TMZ killed all 3 rats in this group. In comparison, none of the corresponding 2 treatment groups of rats administered with NEO212 revealed a significant reduction in WBC count, and all rats continued to thrive.…”

Section: Discussionmentioning

confidence: 73%

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NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma

Minea,

Thein,

Yang

et al. 2024

Neuro-Oncology Advances

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Purpose The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors potential to overcome these limitations. Methods We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow. Results In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity. Conclusion NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 73%

NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma

Minea,

Thein,

Yang

et al. 2024

Neuro-Oncology Advances

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“…NEO212, the bioconjugate of TMZ and POH, has shown promising anticancer activity in a large number of preclinical tumor models, including NPC [ 39 , 40 , 41 , 42 , 43 , 44 ]. However, it has never been investigated in EBV-positive NPC cells, nor is it known whether NEO212 might be able to trigger the lytic cycle and sensitize tumor cells to GCV.…”

Section: Introductionmentioning

confidence: 99%

Activation of Epstein–Barr Virus’ Lytic Cycle in Nasopharyngeal Carcinoma Cells by NEO212, a Conjugate of Perillyl Alcohol and Temozolomide

Hartman-Houstman,

Swenson,

Minea

et al. 2024

Cancers

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The Epstein–Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which is thought to contribute to tumorigenesis. Current treatments are sub-optimal, and recurrence occurs in many cases. An alternative therapeutic concept is aimed at triggering the lytic cycle of EBV selectively in tumor cells as a means to add clinical benefit. While compounds able to stimulate the lytic cascade have been identified, their clinical application so far has been limited. We are developing a novel anticancer molecule, NEO212, that was generated by covalent conjugation of the alkylating agent temozolomide (TMZ) to the naturally occurring monoterpene perillyl alcohol (POH). In the current study, we investigated its potential to trigger the lytic cycle of EBV in NPC cells in vitro and in vivo. We used the established C666.1 cell line and primary patient cells derived from the brain metastasis of a patient with NPC, both of which harbored latent EBV. Upon treatment with NEO212, there was an increase in EBV proteins Zta and Ea-D, key markers of the lytic cycle, along with increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, followed by the activation of caspases. These effects could also be confirmed in tumor tissue from mice implanted with C666.1 cells. Towards a mechanistic understanding of these events, we used siRNA-mediated knockdown of CHOP and inclusion of anti-oxidant compounds. Both approaches blocked lytic cycle induction by NEO212. Therefore, we established a sequence of events, where NEO212 caused reactive oxygen species (ROS) production, which triggered ER stress and elevated the levels of CHOP, which was required to stimulate the lytic cascade of EBV. Inclusion of the antiviral agent ganciclovir synergistically enhanced the cytotoxic impact of NEO212, pointing to a potential combination treatment for EBV-positive cancers which should be explored further. Overall, our study establishes NEO212 as a novel agent able to stimulate EBV’s lytic cycle in NPC tumors, with implications for other virus-associated cancers.

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“…Therefore, malignant WBC affects the bone marrow due to its ability to make the basic components of blood normally and causes a weakening of the immune system. In addition, malignant WBC travels through the bloodstream and causes damage to the liver, spleen, kidneys, brain, etc., and causes other forms of fatal diseases [ 5 ]. The affected WBC type determines the type of leukemia: lymphoid (Acute myeloidleukemia) if the cells are monocytes, or myelogenous (acute lymphoblastic leukemia) if the cells are lymphocytes [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Techniques for the Diagnosis of Acute Lymphoblastic Leukemia Based on Fusion of CNN Features

et al. 2023

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Acute lymphoblastic leukemia (ALL) is one of the deadliest forms of leukemia due to the bone marrow producing many white blood cells (WBC). ALL is one of the most common types of cancer in children and adults. Doctors determine the treatment of leukemia according to its stages and its spread in the body. Doctors rely on analyzing blood samples under a microscope. Pathologists face challenges, such as the similarity between infected and normal WBC in the early stages. Manual diagnosis is prone to errors, differences of opinion, and the lack of experienced pathologists compared to the number of patients. Thus, computer-assisted systems play an essential role in assisting pathologists in the early detection of ALL. In this study, systems with high efficiency and high accuracy were developed to analyze the images of C-NMC 2019 and ALL-IDB2 datasets. In all proposed systems, blood micrographs were improved and then fed to the active contour method to extract WBC-only regions for further analysis by three CNN models (DenseNet121, ResNet50, and MobileNet). The first strategy for analyzing ALL images of the two datasets is the hybrid technique of CNN-RF and CNN-XGBoost. DenseNet121, ResNet50, and MobileNet models extract deep feature maps. CNN models produce high features with redundant and non-significant features. So, CNN deep feature maps were fed to the Principal Component Analysis (PCA) method to select highly representative features and sent to RF and XGBoost classifiers for classification due to the high similarity between infected and normal WBC in early stages. Thus, the strategy for analyzing ALL images using serially fused features of CNN models. The deep feature maps of DenseNet121-ResNet50, ResNet50-MobileNet, DenseNet121-MobileNet, and DenseNet121-ResNet50-MobileNet were merged and then classified by RF classifiers and XGBoost. The RF classifier with fused features for DenseNet121-ResNet50-MobileNet reached an AUC of 99.1%, accuracy of 98.8%, sensitivity of 98.45%, precision of 98.7%, and specificity of 98.85% for the C-NMC 2019 dataset. With the ALL-IDB2 dataset, hybrid systems achieved 100% results for AUC, accuracy, sensitivity, precision, and specificity.

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NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Cited by 5 publications

References 64 publications

NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma

NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma

Activation of Epstein–Barr Virus’ Lytic Cycle in Nasopharyngeal Carcinoma Cells by NEO212, a Conjugate of Perillyl Alcohol and Temozolomide

Hybrid Techniques for the Diagnosis of Acute Lymphoblastic Leukemia Based on Fusion of CNN Features

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