Novel anticancer agent, benzyldihydroxyoctenone, isolated from Streptomyces sp. causes G₁ cell cycle arrest and induces apoptosis of HeLa cells

Abstract

In the course of screening for anticancer agents, a novel active compound, F3-2-5, was isolated from culture broth of Streptomyces sp., KACC91015. Its structure was identified using nuclear magnetic resonance, mass spectrometry, and molecular modeling experiments, and confirmed by total synthesis. The growth of various human cancer cell lines was inhibited in a dose-dependent manner by 0.06-0.48 mM F3-2-5 over 24 h. Its IC 50 values were estimated at 37 µ µ µ µM on HeLa, 72 µ µ µ µM on A549, and 190 µ µ µ µM on HT-29 cells. However, F3-2-5 had no antiproliferative effect on normal lymphocytes and normal fibroblasts used as controls. Moreover, it affected cell cycle regulation and caused apoptosis of the HeLa cells; chromatin condensation and DNA fragmentation were observed in cells exposed to 80 µ µ µ µM F3-2-5. Western blot analysis revealed that F3-2-5 inhibited phosphorylation of retinoblastoma protein (pRb) and reduced expression of cyclindependent kinase-4 and -6, and cyclin D1 and E, while levels of p53 and p21 WAF1/CIP1 increased. Taken O ver the last decade basic cancer research has achieved remarkable advances in the understanding of cancer biology and cancer genetics.(1) Although many anticancer drugs have been developed, most are also toxic to normal cells and tissues, and thus have limited selectivity for cancer cells. Therapeutic use has therefore been restricted to only a few drugs.(2) To overcome these limitations and improve the effectiveness of chemotherapy for cancer, it is necessary not only to isolate new anticancer drugs specifically toxic for cancer cells, but also to identify new targets that destroy cancers when exposed to chemotherapy.The cell cycle in eukaryotes is regulated by a precise balance between positive and negative regulatory components that exert their effects during the G 1 phase. The most critical positively acting components are G 1 cyclins (cyclin Ds and cyclin E) and CDK.(3-6) The G 1 -S transition is dependent on activation of G 1 phase CDK, and phosphorylation of pRb. (7,8) Cyclin D associates with CDK4 and CDK6, causing their activation, which in turn promotes progression through early G 1 phase.(5) Cyclin E and CDK2 proteins act at the transition from the G 1 to the S phase. The G 1 phase-specific cyclins and CDK complexes phosphorylate pRb and release it from its inhibitory association with the transcription factor E2F; the latter then promotes expression of S phase-specific genes. (7,8) In addition, cyclin A is produced in late G 1 phase, and expressed during the S and G 2 phases.(9) The activity of the CDK is inhibited by CKI, such as p21 WAF1/CIP1 and p27 KIP1 thereby blocking cell proliferation. (10)(11)(12)(13) In addition, cell cycle arrest dependent on the tumor suppressor p53 requires transactivation of p21 WAF1/CIP1 . (14) Inhibitors of cell cycle progression have potential as anticancer agents. (15)(16)(17) Apoptosis is also an important determinant of the response of tumors to chemotherapeutic agents.(18) The morphological features of apoptosis include c...

Induction of p53, p21 and apoptosis by silencing the NF90/NF45 complex in human papilloma virus-transformed cervical carcinoma cells

“…p53 is required for efficient activation of apoptosis following irradiation and treatment with chemotherapeutic agents (90). Activation of p53-dependent apoptosis induces Bax expression, resulting in cytochrome c release from mitochondria and caspase-3 activation (91-93). Activated caspase-3 executes apoptosis by inducing cleavage of cellular substrates including PARP (93) and NF90/NF45 depletion in HeLa cells resulted in the accumulation of p53 and the 89-kDa cleavage product of PARP.…”

HY253, a novel decahydrofluorene analog, from Aralia continentalis, induces cell cycle arrest at the G1 phase and cytochrome c-mediated apoptosis in human lung cancer A549 cells

“…Over the last few decades, much attention has been focused on natural products and small chemicals as potential sources of novel anticancer drugs (Park et al, 2006;Kim et al, 2007a,b;Lee et al, 2007). Thus, the identification of potential chemotherapeutic agents using mechanism-based studies holds great promise for elucidating the molecular mechanisms and devising more specific and effective treatments for cancer-related diseases.…”

Apoptosis induction of human leukemia cells by Streptomyces sp. SY-103 metabolites through activation of caspase-3 and inactivation of Akt

“…For example, Macherla et al (4) report that three new pyrrolosesquiterpenes isolated from a culture of Streptomyces sp., obtained from an Alaskan marine sediment, exhibited anti-tumor activity toward the colorectal adenocarcinoma HT-29 and melanoma B16-F10 human cancer cell lines. Moreover, Lee et al (33) reported that F3-2-5 isolated from a culture supernatant of Streptomyces sp. induced apoptosis of HeLa cells.…”