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Borodyansky, Laura; Yz, Li; Pardee, AB; Cj, Li

doi:10.1023/a:1009693517181

Cited by 3 publications

(1 citation statement)

References 26 publications

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“…Multiple checkpoints are built into the machinery of the cell proliferation cycle to protect chromosomal integrity (19)(20). The Ϸ10 16 cell multiplications in the human life time, together with inevitable errors in DNA replication and exposure to ultraviolet rays and mutagens, underscores the requirement for checkpoint functions (22). Major checkpoints occur at G 1 /S phase and at the G 2 /M phase transitions (2,3,(23)(24)(25) where cells make a commitment to repair DNA or to undergo apoptosis (19).…”

Section: Discussionmentioning

confidence: 99%

Potent inhibition of tumor survivalin vivoby β-lapachone plus taxol: Combining drugs imposes different artificial checkpoints

Pinto

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

169

132

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Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of ␤-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after ␤-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. ␤-Lapachone causes cell-cycle delays in late G1 and S phase, and taxol arrests cells at G 2/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone ''collisions'' at cell-cycle checkpoints.A variety of cancer chemotherapeutic drugs has been discovered, but treatment of most human solid tumors remains largely palliative. One way to improve the efficacy of anticancer therapy is to develop optimal combination regimens of chemotherapeutic drugs. In this study, we demonstrate a treatment synergism by combining ␤-lapachone and taxol. This combination resulted in simultaneous cell-cycle checkpoint delays at the G 1 /S and G 2 /M transitions, setting up for apoptosis-prone ''collisions'' (1). We observed very extensive death of various human tumor cells in culture. Importantly, growth of human ovarian tumor cells implanted into immunosuppressed mice was decreased dramatically, without signs of deleterious effects to the mice. Our preliminary experiments also produced dramatic antitumor activity against xenografted human prostate cancer. This study suggests a combination chemotherapy of very great effectiveness as well as a potential avenue for developing anticancer therapies.Cell-cycle checkpoints can be targeted for cancer therapy either by activating checkpoint-mediated apoptosis pathways or by exploiting chemical sensitivity because of loss of checkpoint function (2, 3). Cells arrest in G 2 /M after treatment with DNA-damaging agents, such as chemotherapeutic agents and x-rays (2, 4). Taxol is an anticancer agent with a wide spectrum of activity that blocks cell proliferation in mitosis presumably by interfering with microtubule function (5). Taxol induces a p53-independent G 2 /M arrest (prophase) that triggers the rapid onset of apoptosis (5-8).Drugs that induce G 1 /S checkpoint delays are rarely used. ␤-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione) is a plant product (9, 10). It induces a cell-cycle delay in G 1 and/or ...

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Section: Discussionmentioning

confidence: 99%

Potent inhibition of tumor survivalin vivoby β-lapachone plus taxol: Combining drugs imposes different artificial checkpoints

Pinto

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

169

132

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Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli

2005

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Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension

Zubcevic

Richards

Yang

et al. 2019

Circulation Research

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Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.

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Untitled

Cited by 3 publications

References 26 publications

Potent inhibition of tumor survivalin vivoby β-lapachone plus taxol: Combining drugs imposes different artificial checkpoints

Potent inhibition of tumor survivalin vivoby β-lapachone plus taxol: Combining drugs imposes different artificial checkpoints

Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli

Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension

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