Mechanism Targeted Discovery of Antitumor Marine Natural Products

Nagle, Dale G.; Zhou, Yifeng; Mora, Flor D.; Mohammed, Kaleem A.; Kim, Yong-Pil

doi:10.2174/0929867043364991

Cited by 70 publications

(56 citation statements)

References 255 publications

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“…Increasing evidence shows that marine organisms are a rich source of unique compounds with antitumor properties (24). Several compounds have been isolated that induce apoptosis of cancer cells affecting various cellular components, including tubulin, protein kinases or phosphatases, and topoisomerases (24).…”

Section: Discussionmentioning

confidence: 99%

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Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

et al. 2006

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Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug. Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis. Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (#y m ) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone. #y m disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of #y m and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct MPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D-induced nuclear apoptosis. The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I-mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines. Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells. (Cancer Res 2006; 66(6): 3177-87)

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Section: Discussionmentioning

confidence: 99%

“…Several compounds have been isolated that induce apoptosis of cancer cells affecting various cellular components, including tubulin, protein kinases or phosphatases, and topoisomerases (24). This study defines mitochondria as a new proapoptotic target for marine antitumor drugs.…”

Section: Discussionmentioning

confidence: 99%

Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

et al. 2006

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“…Presently, ∼60% of drugs approved for cancer treatment are of natural origin (3)(4)(5). Large numbers of antimutagens and anticarcinogens that exist in natural products of marine animal and plants inhibit one or more stages of carcinogenesis and prevent or delay cancer development (6).…”

Section: Introductionmentioning

confidence: 99%

Chemopreventive Effects of Frondanol A5, a Cucumaria frondosa Extract, against Rat Colon Carcinogenesis and Inhibition of Human Colon Cancer Cell Growth

Janakiram

Mohammed

Zhang

et al. 2010

Cancer Prevention Research

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Sea cucumber extracts have been widely used to treat individuals with inflammatory conditions in East Asia. The present study has been designed to test potential colon cancer-preventive properties of Frondanol A5, a glycolipid extract from the sea cucumber, Cucumaria frondosa, using in vivo and in vitro models of colon cancer. Chemopreventive efficacy of Frondanol A5 was evaluated on azoxymethane-induced rat colon carcinogenesis using colonic aberrant crypt foci (ACF) as efficacy marker. At 7 weeks of age, groups of rats (12 per group) were fed the AIN-76A diet, and ACFs were induced by azoxymethane (15 mg/kg body weight). Three days after azoxymethane treatment, rats were fed with the diets containing 0, 150, and 450 ppm of Frondanol A5 and continued on the diets for 8 weeks, at which time ACFs were evaluated. Expression levels of proliferating cell nuclear antigen and p21were determined in ACFs. Further, Frondanol A5 (10-120 μg/mL) was studied for its growth-inhibitory and apoptotic effects in the HCT-116 cell line. Dietary administration of 150 and 450 ppm of Frondanol A5 significantly suppressed azoxymethane-induced total colonic ACF formation, approximately 34% to 55% (P < 0.01 to P < 0.0001), and multicrypt aberrant foci (48-68.5%, P < 0.0001) in a dose-dependent manner. ACFs in rats treated with Frondanol A5 showed significant upregulation of p21 WAF1/CIP1 and downregulation of proliferating cell nuclear antigen compared with control group. Frondanol A5 showed growth inhibition at S and G 2 -M phase with a decrease in Cdc25c and an increase in p21 WAF1/CIP with significant apoptosis associated with H2AX phosphorylation and caspase-2 cleavage in HCT116 cells. Overall, Frondanol A5 exhibits potential chemopreventive properties for colon carcinogenesis, which suggests further development of this sea cucumber extract. Cancer Prev Res; 3(1); 82-91. ©2010 AACR.

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“…33 Many antitumor agents can arrest and regulate the cell cycle. 34,35 The results in our report demonstrate that the application of the HSVtk/Tet-On/ GCV system can prolong S phase of MCF-7 cells. Our findings are consistent with the previous reports, showing that S-phase arrest was noticeable and a significant increase in cell granularity was observed in cells treated with either GCV or 5-FC.…”

Section: Discussionmentioning

confidence: 61%

Retrovirus-mediated tk gene therapy of implanted human breast cancer in nude mice under the regulation of Tet-On

Zeng

et al. 2005

Cancer Gene Ther

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Tight regulation of the therapeutic gene expression is critical in gene therapy. In this report, a doxycycline (Dox)-regulated retrovirus-mediated gene expression system was used to study the effects of suicide gene therapy on human breast cancer cell line MCF-7 and the nude mice model of implanted human breast cancer. To render the expression of suicide gene under control, we used two pseudoviruses simultaneously, RevTRE/HSVtk and RevTet-On, to infect MCF-7 cells or xenografts of nude mice. When infected by the pseudoviruses and followed by Dox and Ganciclovir (GCV) treatment, MCF-7 cells were arrested at S phase and the growth was suppressed. We then evaluated the antitumor efficiency of this system in vivo through studying the mice bearing human breast cancer xenografts. Compared with control groups, the HSVtk mRNA level increased significantly in tumor tissues, mass of the tumors shrank remarkably, and tumor necrosis features occurred after treatment with Dox and GCV. These data suggest that suicide gene therapy using the Dox-induced Tet-On-controlled HSVtk gene expression system is a feasible method to treat human breast cancer.

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Mechanism Targeted Discovery of Antitumor Marine Natural Products

Cited by 70 publications

References 255 publications

Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

Chemopreventive Effects of Frondanol A5, a Cucumaria frondosa Extract, against Rat Colon Carcinogenesis and Inhibition of Human Colon Cancer Cell Growth

Retrovirus-mediated tk gene therapy of implanted human breast cancer in nude mice under the regulation of Tet-On

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