Broad Spectrum Of Antitumor Activity Research Articles

Enabling oral novel Taxanes-based Chemotherapy with Lipophilic prodrug Self-nanoemulsifying drug delivery system

Larotaxel (LTX) and SB-T-1214 (SBT), two new synthetic experimental toxoids, have shown broad-spectrum antitumor activity, especially against tumors that are resistant to other drugs. However, their poor solubility, membrane permeability, and first-pass effect limits their use in oral administration. We designed and synthesized two long-chain triglyceride-mimic prodrugs of LTX (LTXSSTG) and SBT (SBTSSTG), which are bridged by disulfide bonds and efficiently incorporated them into Self-nanoemulsifying drug delivery system (SNEDDS). These prodrugs can bypass hepatic metabolism by entering the blood through intestinal lymphatic transport, following a similar oral absorption pathway to dietary lipids. It was found that LTXSSTG and SBTSSTG significantly improved oral bioavailability (about 4.5-fold for LTX and 3.4-fold for SBT) compared to their solution forms. Moreover, with LTXSSTG and SBTSSTG incorporating reduction stimulus-responsive spacer were much more effective in suppressing tumor growth in vivo with eliminated adverse effects than solution form. To sum up, this strategy provides a new avenue to enhance oral delivery of new toxoids.

A Mini-Review on the Structural Characteristics and Anticancer Activity of Nagilactones

Abstract: Natural products provide abundant resources for the development of new drugs. Podocarpus nagi is an arbor of Podocarpus L'Hér. ex Persoon. Its fruits, leaves, and roots exhibit a broad spectrum of pharmacological activities (such as antitumor, plant growth regulation, termite killing, and insect larval toxicity), which have been used in Yao folk for a long history. Nagilactone is one of the key components discovered in Podocarpus nagi, which has a variety of structures and a broad spectrum of antitumor activities. In this mini-review, the structures and spectral characteristics, together with the antitumor activities and the structure-activity relationships of nagilactones, are summarized by searching the database in order to provide detailed references for researchers to elucidate and modify their structures.

Unleashing the antitumor power of cyclophosphamide by arabinogalactan and aptamer conjugation

Cyclophosphamide (CPA) (2-oxo-2-di(β-chloroethyl)amino tetrahydro-2,1,3-phosphoxazine) is an alkylating cytostatic compound with a broad spectrum of antitumor activity. Despite its efficacy, the clinical application of CPA is hindered by the significant occurrence of adverse side effects. To address these limitations, a promising approach involves the mechanochemical treatment of CPA with arabinogalactan (AG) to facilitate the dispersion of the drug within the AG matrix. AG stands out from other polymers due to its uniformity, low molecular weight, water solubility, and ability to form drug conjugates, thereby enhancing their therapeutic potency. Moreover, AG possesses immune-modulating properties that have the potential to counteract the immunosuppressive effects induced by CPA. By means of mechanical treatment, we successfully obtained CPA-AG complexes with a CPA:AG ratio of 1:10. These complexes were further modified with As42 aptamers that specifically target Erlich ascites cells. Aptamers, a novel class of oligonucleotide ligands obtained through SELEX technology, possess high affinity and specificity for binding to various receptors. An ascitic form of Ehrlich carcinoma was chosen as an in vitro and in vivo tumor model due to its notable drug resistance. In vitro and in vivo evaluations were conducted to compare the antitumor activity of both the CPA-AG and CPA-AG-As42 complexes with pure CPA. In vitro experiments revealed that the CPA-AG complex displayed superior antitumor activity compared to pure CPA, leading to complete tumor cell death primarily through necrosis. Notably, no toxic effects were observed with the CPA-AG and CPA-AG-As42 complexes, and they significantly prolonged the lifespan of tumor-bearing mice by more than 3.5 times. Histological studies further supported the antitumor efficacy of these complexes. These results underscore the potential of utilizing CPA-AG mechanocomposites, functionalized with aptamers, for the targeted delivery of CPA to tumors.

DHRS2-induced SPHK1 downregulation contributes to the cell growth inhibition by Trichothecin in colorectal carcinoma

BackgroundDeregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression.Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity. MethodsWe evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of SPHK1 expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN. ResultsWe demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to SPHK1 mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC. ConclusionsThe present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.

Regulation of Safracin Biosynthesis and Transport in Pseudomonas poae PMA22.

Pseudomonas poae PMA22 produces safracins, a family of compounds with potent broad-spectrum anti-bacterial and anti-tumor activities. The safracins' biosynthetic gene cluster (BGC sac) consists of 11 ORFs organized in two divergent operons (sacABCDEFGHK and sacIJ) that are controlled by Pa and Pi promoters. Contiguous to the BGC sac, we have located a gene that encodes a putative global regulator of the LysR family annotated as MexT that was originally described as a transcriptional activator of the MexEF-OprN multidrug efflux pump in Pseudomonas. Through both in vitro and in vivo experiments, we have demonstrated the involvement of the dual regulatory system MexT-MexS on the BGC sac expression acting as an activator and a repressor, respectively. The MexEF-OprN transport system of PMA22, also controlled by MexT, was shown to play a fundamental role in the metabolism of safracin. The overexpression of mexEF-oprN in PMA22 resulted in fourfold higher production levels of safracin. These results illustrate how a pleiotropic regulatory system can be critical to optimizing the production of tailored secondary metabolites, not only through direct interaction with the BGC promoters, but also by controlling their transport.

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities.

A series of novel thiazole-based chalcones were evaluated for their anticancer activity as potential tubulin polymerization inhibitors. In vitro anticancer screening for the thiazole derivatives 2a-2p exhibited broad-spectrum antitumor activity against various cancer cell lines particularly Ovar-3 and MDA-MB-468 cells with a GI50 range from 1.55 to 2.95 μΜ, respectively. Compound 2e demonstrated significant inhibition of tubulin polymerization, with an IC50 value of 7.78 μM compared to Combretastatin-A4 (CA-4), with an IC50 value of 4.93 μM. Molecular docking studies of compounds 2e, 2g, and 2h into tubulin further supported these findings, revealing that they bind effectively to the colchicine binding site, mirroring key interactions exhibited by CA-4. Computational predictions suggested favorable oral bioavailability and drug-likeness for these compounds, highlighting their potential for further development as chemotherapeutic agents.

6-Shogaol improves sorafenib efficacy in colorectal cancer cells by modulating its cellular accumulation and metabolism

Carcinoma of the colon and rectum, also known as colorectal cancer, ranks as the third most frequently diagnosed malignancy globally. Sorafenib exhibits broad-spectrum antitumor activity against Raf, VEGF, and PDGF pathways in hepatocellular, thyroid, and renal cancers, but faces resistance in colorectal malignancies. 6-Shogaol, a prominent natural compound found in Zingiberaceae, exhibits antioxidant, anti-inflammatory, anticancer, and antiemetic properties. We investigated the influence of 6-shogaol on sorafenib’s cytotoxic profile against colorectal cancer cell lines (HT-29, HCT-116, CaCo-2, and LS174T) through its effects on cellular accumulation and metabolism. Cytotoxicity was assessed using the sulpharodamine B assay, caspase-3 and c-PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity. 6-Shogoal showed considerable cytotoxicity with decreased IC50 in colorectal cancer cell lines. Combining sorafenib and 6-shogaol increased c-PARP and pro-caspase-3 concentrations in HCT-116 cells compared to sorafenib alone. In combination, pro-caspase-3 concentrations were decreased in CaCo-2 cells compared to alone. Sorafenib combinations with 6-shogaol showed a significant drop in cell cycle distribution from 16.96±1.10 % to 9.16±1.85 %, respectively. At 100 µM, sorafenib and 6-shogaol showed potent and significant activity with intra-cellular rhodamine concentration on P-gp efflux activity in CRC cell lines. In conclusion, 6-shogaol substantially improved the cytotoxic profile of sorafenib by affecting its cellular uptake and metabolism. Future research should focus on dosage optimization and formulation and evaluate the efficacy and safety of the combination in animal models with colorectal cancer.

Anti-tumor effect and hepatotoxicity mechanisms of psoralen.

In recent years, natural products have gradually become an important source for new drug development due to their advantages of multi-components, multi-targets, and good safety profiles. Psoralen, a furanocoumarin compound extracted from the traditional Chinese medicine psoralea corylifolia, is widely distributed among various plants. It has attracted widespread attention in the research community due to its pharmacological activities, including antitumor, anti-inflammatory, antioxidant, and neuroprotective effects. Studies have shown that psoralen has broad spectrum anti-tumor activities, offering resistance to malignant tumors such as breast cancer, liver cancer, glioma, and osteosarcoma, making it a natural, novel potential antitumor drug. Psoralen mainly exerts its antitumor effects by inhibiting tumor cell proliferation, inducing apoptosis, inhibiting tumor cell migration, and reversing multidrug resistance, presenting a wide application prospect in the field of antitumor therapy. With the deepening research on psoralea corylifolia, its safety has attracted attention, and reports on the hepatotoxicity of psoralen have gradually increased. Therefore, this article reviews recent studies on the mechanism of antitumor effects of psoralen and focuses on the molecular mechanisms of its hepatotoxicity, providing insights for the clinical development of low-toxicity, high-efficiency antitumor drugs and the safety of clinical medication.

Sponge-derived alkaloid AP-7 as a sensitizer to cisplatin in the treatment of multidrug-resistant NSCLC via Chk1-dependent mechanisms.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo. These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC.

Octreotide modified liposomes that co-deliver paclitaxel and neferine effectively inhibit ovarian cancer metastasis by specifically binding to the SSTR2 receptors

Early detection of ovarian cancer is challenging, leading to high mortality rates. Paclitaxel has broad-spectrum anti-tumor activity and has been used clinically for the treatment of various cancers. However, the severe side effects of paclitaxel limit its use at high doses. Hence, it is imperative to develop a novel anti-neoplastic agent that can enhance therapeutic efficacy and selectively target tumor sites, thereby mitigating systemic toxicity. In this study, lipid nanoparticles with surface-modified octreotide were constructed by a thin film dispersion method to co-encapsulate paclitaxel and neferine, which are lipophilic compounds, within the phospholipid bilayer, improving their solubility. Liposomes modified with octreotide can increase its active targeting to SKOV3 cells through SSTR-mediated endocytosis and prolong the drug circulation time in vivo. The potential synergistic effects of paclitaxel and neferine were confirmed and quantified by Synergyfinder analysis software. In vitro experimental results showed that neferine can synergistically enhance the cytotoxicity of paclitaxel against human ovarian cancer cells, exerting anti-proliferative, apoptosis-inducing, invasion-suppressing, and angiogenesis-disrupting effects. The in vivo targeting and tumor inhibition of Octreotide-modified liposomes that co-deliver paclitaxel and neferine (OCT-PTX/Nef-Lips) were investigated in mice xenografted with SKOV3 cells. In vivo pharmacodynamic evaluation demonstrated the safe and effective ability of OCT-PTX/Nef-Lips to inhibit tumor volume growth, disrupt tumor tissue morphology, induce apoptosis in tumor cells, and suppress their proliferation. Furthermore, angiogenesis was inhibited through down-regulation of angiogenesis-related proteins (TIE-2, VEGFA, VE-Cadherin, Ang-2).

Anticancer Potential and Molecular Targets of Pristimerin in Human Malignancies.

The growing global burden of malignant tumors with increasing incidence and mortality rates underscores the urgent need for more effective and less toxic therapeutic options. Herbal compounds are being increasingly studied for their potential to meet these needs due to their reduced side effects and significant efficacy. Pristimerin (PS), a triterpenoid from the quinone formamide class derived from the Celastraceae and Hippocrateaceae families, has emerged as a potent anticancer agent. It exhibits broad-spectrum anti-tumor activity across various cancers such as breast, pancreatic, prostate, glioblastoma, colorectal, cervical, and lung cancers. PS modulates several key cellular processes, including apoptosis, autophagy, cell migration and invasion, angiogenesis, and resistance to chemotherapy, targeting crucial signaling pathways such as those involving NF-κB, p53, and STAT3, among others. The main objective of this review is to provide a comprehensive synthesis of the current literature on PS, emphasizing its mechanisms of action and molecular targets with the utmost clarity. It discusses the comparative advantages of PS over current cancer therapies and explores the implications for future research and clinical applications. By delineating the specific pathways and targets affected by PS, this review seeks to offer valuable insights and directions for future research in this field. The information gathered in this review could pave the way for the successful development of PS into a clinically applicable anticancer therapy.

Abstract LB165: GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS(on) inhibitor with broad spectrum anti-tumor activities

Abstract KRAS has recently become druggable with the approval of two KRAS G12C inhibitors - sotorasib and adagrasib. However, current SIIP-based KRAS inhibitors preferentially target the inactive, GDP-bound KRAS and thus are susceptible to adaptive resistance due to MAPK pathway reactivation. Furthermore, RTK pathway alterations frequently emerge to cause acquired resistance. These drawbacks limit the rate and duration of anti-tumor response. Developing more robust small molecule RAS (on) inhibitors that target active, GTP-bound RAS proteins is a promising new approach to enhance clinical benefits. Here we report preclinical characterization of a novel RAS (on) inhibitor - GFH547, designed to treat cancers carrying multiple RAS mutations. In biochemical assays, GFH547 disrupted the binding of GMPPNP-bound G12V, G12D or wild type KRAS to RAF1 in a CypA-dependent manner, as the inhibitory effect was significantly abolished in the absence of CypA. GFH547 suppressed phosphor-ERK1/2 (p-ERK) levels in KRAS G12V- and G12D-mutated cells with IC50s < 1 nM, and demonstrated potent tumor-suppressive effect in 29 cancer cell lines carrying diverse KRAS (G12A, G12C, G12V, G12R, G12S or G13D), NRAS (G12D or Q61L) or HRAS (Q61H) mutations, with IC50s of 0.04-1.9 nM. In addition, GFH547 was also cytotoxic in 9 cancer cell lines carrying EGFR or FGFR2/3 amplification, mutation or fusion, with IC50s of 0.12-198 nM. Conversely, GFH547 was inactive against 4 BRAF V600E-mutated, RAS-independent cancer cell lines. In KRAS-mutated xenograft models, oral administration of GFH547 elicited rapid and potent inhibition of intratumoral p-ERK levels, and led to tumor regression at dose levels as low as 1 mg/kg QD. In contrast to sotorasib and adagrasib, GFH547 was not susceptible to RTK-reactivation following EGF stimulation, and remained effective against cell lines carrying KRAS mutations that confer acquired resistance to SIIP-based KRAS inhibitors. At 10 μM, GFH547 showed no off-target activity in 72-kinase selectivity and SafetyScreen44 panels. GFH547 has a bioavailability of 76% and was well tolerated in mice, with an estimated therapeutic index >20. Taken together, by hijacking CypA to block oncogenic RAS proteins broadly in their active forms, GFH547 represents a new generation of RAS inhibitors that are superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance. The compound demonstrated strong therapeutic activities in tumors with activating RAS and RTK mutations/alterations. Based on these promising results, we are advancing a CypA-binding panRAS(on) inhibitor into the clinic as targeted therapy for cancers addicted to RAS pathways. Citation Format: Feng Yan, Jichen Zhao, Tao Liang, Tao Jiang, Chonglan Lin, Ling Peng, Kai Ma, Huabin Yang, Wan He, Zhen Li, Leitao Zhang, Xiaoming Xu, Yanhui Zhao, Xiaohui Zhang, Yonghong Ni, Qiang Liu, Jinting Gao, Fubo Xie, Xueyan Gao, Xiaoling Lan, Li Wang, Jingyang Zhang, Hongcan Ren, Dong Liu, Siyuan Le, Fusheng Zhou, Jiong Lan, Qiang Lu. GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS(on) inhibitor with broad spectrum anti-tumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB165.

Abstract 1968: Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers

Abstract Fibroblast growth factor receptor 2 (FGFR2) is a clinically validated target and frequently altered in many solid tumors. The resulting oncogenic driver alterations often drive multiple solid tumors. Therefore, targeting FGFR2 has broad therapeutic potential. Currently, only pan-FGFR inhibitors are approved for FGFR2-driven intrahepatic cholangiocarcinoma, but not for other FGFR2-driven cancers. Due to the severe on-target toxicity associated with inhibition of FGFR1 and FGFR4, the use of the pan-FGFR inhibitors has been very limited. Thus, developing a selective FGFR2 inhibitor addresses the unmet medical need as the treatment options for FGFR2-altered cancers remain limited. Here we report the discovery and characterization of a highly selective FGFR2 inhibitor, ACE-16229210. This molecule potently inhibits FGFR2 (IC50 = 6.2 nM) and exhibits excellent selectivity (>133-fold) over other FGFR1 and FGFR4 in biochemical assays. It also potently (IC50 <1 nM) and selectively (≥500-fold) inhibits FGFR2-induced ERK phosphorylation in multiple cancer cell lines harboring FGFR2 fusions, amplification, and mutations, but not those harboring FGFR1, FGFR3, or FGFR4 genetic alterations (IC50 > 460 nM). Furthermore, this molecule, when evaluated in a panel of 24 cell lines, demonstrates potent anti-proliferative activity against the cell lines harboring FGFR2, but not FGFR3, and especially FGFR1, or FGFR4 genetic alterations. Thus, ACE-16229210 is a potent and selective FGFR2 inhibitor. Interestingly, it exhibits the most potent activity against gatekeeper and molecular brake mutations followed by fusions, amplification, and activation loop mutations. This molecule shows a robust broad spectrum of antitumor activity with significant tumor regression at low doses (1-10 mg/kg) in several tumor xenograft and PDX models representing the major FGFR2 relevant tumor histologies including gastric, breast, ovarian, and endometrial cancers harboring clinically important FGFR2 driver alterations with a well-defined pharmacokinetic/pharmacodynamic relationship. This molecule also demonstrates strong synergistic effects when combined with irinotecan and fulvestrant in a gastric tumor model and a breast cancer PDX model harboring FGFR2 amplification, respectively. Finally, ACE-16229210 did not significantly affect serum phosphorus levels in animals at the exposure levels that are >100-fold higher than the efficacious AUC, further confirming its excellent selectivity over FGFR1. Taken together, these in vitro and in vivo studies show that ACE-16229210 is a potent and selective FGFR2 inhibitor with the potential to be developed into a more effective treatment option for multiple cancers harboring FGFR2 oncogenic driver alterations. Citation Format: Wenqian Li, Bin Liu, Junmei Wang, Tinggui Yin, Kuo-Long Yu, Sanjeev Kumar, Zhiming Wen, Genshi Zhao, Weitao Pan. Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1968.

Abstract 598: HSK42360: A potent, brain permeable, BRAF paradox breaker for the treatment of BRAF-driven cancers

Abstract Mutations in the BRAF gene are among the most common identified in human cancers approximately 7% of all cancers evaluated, including 70% of melanomas, 50% of thyroid-like cancers, 10% to 20% of colorectal cancers, 13% of serous ovarian cancers, 3-7% of non-small-cell lung cancers, and most recently, hairy cell leukemia. Approved BRAF inhibitors (or +MEKi) against BRAFV600E/K improved initial clinical efficacy. However intrinsic and acquired resistance often arise through BRAF paradoxical activation, limiting durable responses to current BRAF inhibitors. In addition, Approved BRAFi responds poorly to patients with BRAF mutant gliomas or brain metastases, mainly due to limited brain permeability. More effective therapeutic options are therefore needed. To address this clinical challenge, we developed a potent, brain-penetrating paradox breaker HSK42360, as a promising therapy for patients with BRAFV600E mutation, progression or brain metastases following treatment with approved BRAFi or BRAFi/MEKi therapies. HSK42360 is a potent BRAFV600E inhibitor with IC50 value of 5 nM at enzymatic level. Further characterization showed that HSK42360 did not induce homodimer or heterodimer of CRAF with CRAF or BRAF and thereby blocked reactivation of the MAPK pathway in HCT116 cells, whereas Dabrafenib significantly induced RAF dimerization and MAPK reactivation. HSK42360 exhibited significant anti-proliferation activity against multiple tumor cell lines with BRAFV600E, including A375 (melanoma), DU4475 (breast cancer), and COLO205 (colon cancer), but was highly selective for BRAF wild-type cells. HSK42360 was administered orally once daily and showed broad-spectrum antitumor activity in the COLO205 and A375 CDX models. Immunohistochemistry showed a close correlation between the inhibition of tumor growth and ERK1/2 phosphorylation in A375 CDX tumor tissues. To explored the impact of HSK42360 in a brain micro-metastasis model aimed at mimicking early CNS metastatic spread, tumor progression was monitored through BLI (full name) imaging, which revealed that HSK42360 was highly brain penetrant with Kp,uu greater than 1 and triggered potent antitumor activity and prolonged survival in brain metastatic models of melanoma. We next tested the hypothesis that HSK42360 could retain activity in models presenting RAF dimer-driven resistance. Surprisingly, HSK42360 demonstrated promising antitumor effects in the first gen-resistant NRASmA375(NRASQ61K, BRAFV600E) CDX model, supporting its use as a follow-on therapy for current BRAFi resistance. Collectively, these preclinical studies validated that HSK42360 is a novel brain-permeable BRAF paradox breaker that exhibits outstanding antitumor activity in brain metastasis and RAF dimer-driven resistance. Citation Format: Shidong Gao, Yangguang Li, Ju Wang, Pingming Tang, Zongjun Shi, Yao Li, Pangke Yan. HSK42360: A potent, brain permeable, BRAF paradox breaker for the treatment of BRAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 598.

Methylseleninic acid inhibits human glioma growth in vitro and in vivo by triggering ROS-dependent oxidative damage and apoptosis.

Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.

Development of an Efficient Synthetic Process for Irisquinone

AbstractIrisquinone is a tumor radiotherapy sensitizer and has been found to have broad-spectrum antitumor activity in recent years. The current acquisition method of extracting and purifying from semen irisis has greatly limited its wide application and activity study deeply. In this work an efficient route for the synthesis of the irisquinone was investigated to solve the source of it. The target compound was synthesized by 5-step reactions to Wittig reaction, reduction, oxidation, Wittig reaction, and oxidation using 3,5-dimethoxycarboxaldehyde as the starting material with an overall yield of 48%. The key factors such as the ratio of raw materials, temperatures, solvents, reaction times, and types of base for the main reactions were optimized. In addition, the deprotection and reduction were completed with Pd/C catalytic simultaneously when compound 2 was synthesized from compound 1. In the last reaction, the 3,5-dimethoxybenzene moiety of compound 4 was directly oxidized to 6-methoxy-1,4-benzoquinone by K3[Fe(CN)6]/H2O2 without the need to selectively remove the methyl protecting group, which were the innovative points in the experimental route design of the irisquinone synthesis. This work has opened new perspectives for the artificial synthesis and the development of irisquinone.

Antimicrobial and antitumor properties of anuran peptide temporin-SHf induce apoptosis in A549 lung cancer cells

Temporin-SHf is a linear, ultra-short, hydrophobic, α-helix, and phe-rich cationic antimicrobial peptide. The antitumor activities and mechanism of temporin-SHf-induced cancer cell death are unknown. The temporin-SHf was synthesized by solid-phase Fmoc chemistry and antimicrobial and antitumor activities were investigated. Temporin-SHf was microbiocidal, non-hemolytic, and cytotoxic to human cancer cells but not to non-tumorigenic cells. It affected the cancer cells' lysosomal integrity and caused cell membrane damage. The temporin-SHf inhibited A549 cancer cell proliferation and migration. It is anti-angiogenic and causes cancer cell death through apoptosis. The molecular mechanism of action of temporin-SHf confirmed that it kills cancer cells by triggering caspase-dependent apoptosis through an intrinsic mitochondrial pathway. Owing to its short length and broad spectrum of antitumor activity, temporin-SHf is a promising candidate for developing a new class of anticancer drugs.

Synthesis, enzyme inhibition assay, and molecular modeling study of novel pyrazolines linked to 4-methylsulfonylphenyl scaffold: antitumor activity and cell cycle analysis.

Antitumor activity using 59 cancer cell lines and enzyme inhibitory activity of a newly synthesized pyrazoline-linked 4-methylsulfonylphenyl scaffold (compounds 18a-q) were measured and compared with those of standard drugs. Pyrazolines 18b, 18c, 18f, 18g, 18h, and 18n possessed significant antitumor activity, with a positive cytotoxic effect (PCE) of 22/59, 21/59, 21/59, 48/59, 51/59, and 20/59, respectively. The cancer cell lines HL60, MCF-7, and MDA-MB-231 were used to measure the IC50 values of derivatives 18c, 18g, and 18hvia the MTT assay method, and the results were compared with those of reference drugs. Derivatives 18g and 18h showed potent and broad-spectrum antitumor activities against HL60 (IC50 of 10.43, 8.99 μM, respectively), MCF-7 (IC50 of 11.7 and 12.4 μM, respectively), and MDA-MB-231 (IC50 of 4.07 and 7.18 μM, respectively). Compound 18c exhibited strong antitumor activity against HL60 and MDA-MB-231 cell lines with IC50 values of 8.43 and 12.54 μM, respectively, and moderate antitumor activity against MCF-7 cell lines with an IC50 value of 16.20 μM. Compounds 18c, 18g, and 18h remarkably inhibited VEGFR2 kinase (IC50 = 0.218, 0.168, and 0.135 μM, respectively) compared with the reference drug sorafenib (IC50 = 0.041 μM). Compounds 18g and 18h effectively inhibited HER2 kinase (IC50 = 0.496 and 0.253 μM, respectively) compared with erlotinib (IC50 = 0.085 μM). Compound 18h inhibited EGFR kinase (IC50 = 0.574 μM) with a potency comparable with that of the reference drug erlotinib (IC50 = 0.105 μM). Pyrazolines 18c, 18f, and 18h arrested the S/G2 phase of the cell cycle in HL-60 cells. In addition, derivatives 18c, 18f, and 18h revealed lower Bcl-2 protein expression anti-apoptotic levels and higher Bax, caspase-3, and caspase-9 expression levels. Molecular docking studies of derivative 18h into the binding sites of EGFR, HER2, and VEGFR2 kinases explored the interaction mode of these pyrazoline derivatives and their structural requirements for antitumor activity.

The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors

BackgroundOncolytic viruses are now well recognized as potential immunotherapeutic agents against cancer. However, the first FDA-approved oncolytic herpes simplex virus 1 (HSV-1), T-VEC, showed limited benefits in some patients in clinical trials. Thus, the identification of novel oncolytic viruses that can strengthen oncolytic virus therapy is warranted. Here, we identified a live-attenuated swine pseudorabies virus (PRV-LAV) as a promising oncolytic agent with broad-spectrum antitumor activity in vitro and in vivo.MethodsPRV cytotoxicity against tumor cells and normal cells was tested in vitro using a CCK8 cell viability assay. A cell kinase inhibitor library was used to screen for key targets that affect the proliferation of PRV-LAV. The potential therapeutic efficacy of PRV-LAV was tested against syngeneic tumors in immunocompetent mice, and against subcutaneous xenografts of human cancer cell lines in nude mice. Cytometry by time of flight (CyTOF) and flow cytometry were used to uncover the immunological mechanism of PRV-LAV treatment in regulating the tumor immune microenvironment.ResultsThrough various tumor-specific analyses, we show that PRV-LAV infects cancer cells via the NRP1/EGFR signaling pathway, which is commonly overexpressed in cancer. Further, we show that PRV-LAV kills cancer cells by inducing endoplasmic reticulum (ER) stress. Moreover, PRV-LAV is responsible for reprogramming the tumor microenvironment from immunologically naïve (“cold”) to inflamed (“hot”), thereby increasing immune cell infiltration and restoring CD8+ T cell function against cancer. When delivered in combination with immune checkpoint inhibitors (ICIs), the anti-tumor response is augmented, suggestive of synergistic activity.ConclusionsPRV-LAV can infect cancer cells via NRP1/EGFR signaling and induce cancer cells apoptosis via ER stress. PRV-LAV treatment also restores CD8+ T cell function against cancer. The combination of PRV-LAV and immune checkpoint inhibitors has a significant synergistic effect. Overall, these findings point to PRV-LAV as a serious potential candidate for the treatment of NRP1/EGFR pathway-associated tumors.

Design, synthesis, and biological evaluation of simplified tetrahydroisoquinoline analogs.

A series of tetrahydroisoquinoline derivatives were prepared and their antitumor activity was studied against several human carcinoma cell lines, including Ketr3, BEL-7402, BGC-823, KB, HCT-8, MCF-7, HeLa, A2780, A549, and HT-1080. Compound 20, an analog of phthalascidin 650, exhibited good broad-spectrum antitumor activity in vitro. However, compounds 19 and 21, in which the side chains at C-22 are simplified, showed no obvious antitumor activity, indicating that the C-22 side chain of this type of compound has a greater impact on its activity. The difference in the in vivo activity between compound 20 and phthalascidin 650 also shows a significant effect of the substituents on the skeleton structure on the in vivo activity.