Background/Aim: In a screen of compounds to selectively suppress the growth of cancer spheroids, which contained mutant (mt) KRAS, NPD10621 was discovered and associated derivatives were investigated. Materials and Methods: Spheroid areas from HCT116-derived HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were treated with 12 NPD10621 derivatives and measured in three-dimensional floating (3DF) cultures. Several cancers were treated with NPD1018 (pyra-metho-carnil: PMC) in 3DF cultures. In a nude mouse assay, 50% cell growth inhibition (GI 50 ) values were determined. Results: From these 12 derivatives, PMC was the most effective inhibitor of HKe3-mtKRAS spheroid growth with the least toxicity. Furthermore, PMC-mediated growth suppression was observed in all tested cancer cell lines, independent of tissue context, driver gene mutations, and drug resistance, suggesting that the PMC target(s) was crucial for cancer growth in a context-independent manner. The GI 50 value of PMC in nude mice assay was 7.7 mg/kg and nude mice that were administered 40 mg/kg PMC for 7 days did not show any abnormal blood cell count values. Conclusion: PMC is a low-toxicity compound that inhibits the growth of different tumor cell types.The human gene encoding KRAS GTPase is among the most frequently mutated cancer drivers (1). Mutant KRAS (mtKRAS), with activating missense mutations, constitutively activates numerous signaling pathways implicated in cell proliferation and survival, and therefore promotes cancer development, metastasis, and therapy resistance (2, 3). Oncogenic KRAS mutations are frequently identified in hard-to-treat cancers such as pancreatic cancers (86%-96% with oncogenic KRAS mutations) (4), colorectal cancers (CRCs) (40%-54%), and non-small cell lung cancers (15%-20%) (5, 6). Hence, considerable efforts have been focused on developing drugs targeting the activated KRAS or KRAS-related tumor-promoting pathways.Recently, AMG510 (sotorasib), which directly targets the KRAS G12C mutation, was developed (7) and approved by the United States Food and Drug Administration. However, the G12C mutation accounts for approximately 10% of mutations in oncogenic mtKRAS (5, 7-12); therefore, oncogenic mtKRAS remains an "undruggable" target. In addition, while molecular-targeted drugs against KRASrelated signaling factors (such as BRAF and EGFR) are clinically approved and effective, intrinsic or acquired drug resistance is an important unsolved issue in the present cancer treatment. Therefore, novel agents, which overcome KRAStargeted therapy limitations, are highly anticipated.Different natural compounds have served as important discovery sources for effective anticancer agents, while canonical anticancer agents from natural products, such as 3993
Background/Aim: Pyra-Metho-Carnil (PMC) has been identified as a novel candidate compound for treating numerous malignancies; however, its mechanism of action remains unknown. In this study, we conducted RNA-sequencing (RNA-seq) analyses to elucidate the mechanism of PMC against human colorectal cancer cells harboring mutant KRAS (mtKRAS). Materials and Methods: RNA-seq analyses of the HKe3-wild-type KRAS and HKe3-mtKRAS spheroids treated with DMSO or PMC for 6 days were performed. Results: RNAseq data suggested that PMC treatment suppresses the aerobic glycolysis pathway in HKe3-mtKRAS spheroids through the down-regulation of the HIF1 pathway. Indeed, treatment with PMC markedly suppresses the absorption of glucose by spheroids and the secretion of lactate from them. Conclusion: PMC suppresses growth of cancer spheroid through downregulation of cancer-specific glucose metabolism. KRAS is a key molecule in the aberrant proliferation and malignant progression of cancer cells (1, 2).Activated KRAS or KRAS-related tumor-promoting pathways are important targets for cancer therapeutics.Inhibitors of KRAS with specific mutations such as G12C (sotorasib) have been developed; however, 10% of oncogenic KRAS mutations are attributable to the G12C mutation (3-5). In addition, the efficacy of direct KRAS inhibitors and inhibitors of downstream KRAS signals targeting BRAF and MEK is temporal because cells often acquire drug resistance (6-8). Remarkably, conventional cancer treatments exhibited considerable toxicity when administered as therapy (9). To overcome these problems, we developed two isogenic colorectal cancer-derived HKe3 cell lines, whose endogenous allele of mutant KRAS (mtKRAS) G13D was disrupted and reexpressed either wild-type KRAS (wtKRAS; normal cell model) or mtKRAS G13D (cancer cell model) (10,11). Further, we conducted a screening process on these cells to find natural compounds that selectively and effectively eliminate cancer spheroids. We identified a compound, Pyra-Metho-Carnil (PMC), which exhibits a specific antitumor activity for HKe3-mtKRAS spheroids (12). Furthermore, PMC demonstrates growth-restricting properties against cancer spheroids with various genetic mutations, regardless of tissue type ( 12), suggesting that PMC can target common features of cancer spheroids. However, the exact mechanisms of how PMC exerts its effects remain uncertain. In this study, we used RNAsequencing (RNA-seq) analyses on cancer spheroids treated with PMC for 6 days and revealed the mechanisms underlying the PMC-induced tumor growth inhibition. Materials and MethodsCompounds. PMC (IUPAC Name: 1-{3-[(3,5-dimethylpyrazol-1yl)methyl]-4-methoxyphenyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indole) was synthesized by Namiki Shoji Co., Ltd. (Tokyo, Japan) as described previously (12).
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