Phase I/II Study of AT-101 with Topotecan in Relapsed and Refractory Small Cell Lung Cancer

Heist, Rebecca S.; Fain, J.; Chinnasami, Bernard; Khan, Waseem Asrar; Molina, Julian R.; Sequist, Lecia V.; Temel, Jennifer S.; Fidias, Panos; Brainerd, Valari; Leopold, Lance; Lynch, Thomas J.

doi:10.1097/jto.0b013e3181e8f4dc

Cited by 77 publications

(42 citation statements)

References 25 publications

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“…Gossypol can overcome gemcitabine resistance in cell lines with a high level of Bcl-2 expression and sensitize cancer cells to TRAIL or docetaxel in combination drug therapy [20][21][22]. Currently, gossypol is being evaluated in phase I and II clinical trials for use as a single agent or in combination with other anti-tumor agents in a variety of hematologic, lymphoid, and solid tumor malignancies [23,24]. However, the potential of gossypol to improve 5-FU sensitivity of colon cancer cells is unclear.…”

Section: Introductionmentioning

confidence: 99%

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

Yang

et al. 2015

Cancer Chemother Pharmacol

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Section: Introductionmentioning

confidence: 99%

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

Yang

et al. 2015

Cancer Chemother Pharmacol

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“…These so-called BH3 mimetics directly interfere with the protein structure of Bcl-2, Bcl-xL, Bcl-w or Mcl-1 and thus inhibit the antiapoptotic function of these molecules [124]. Among them, the preclinically most intensively studied compound obatoclax (GX15–070) [135,136,137] and gossypol (AT-101) [138,139,140] showed very promising results and are currently undergoing clinical testing. ABT-737 and its orally available derivative navitoclax (ABT-263) bind to Bcl-2, Bcl-xL and Bcl-w and sequester proapoptotic BH3 domain proteins, which promotes the oligomerization of proapoptotic Bax and Bak [141].…”

Section: Novel Compounds Enhancing Cell Death Responsesmentioning

confidence: 99%

Apoptosis-Modulating Drugs for Improved Cancer Therapy

Ocker

Höpfner

2012

Eur Surg Res

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Resistance to cell death induction has been recognized as a hallmark of cancer. Increasing understanding of the underlying molecular events regulating different cell death mechanisms like apoptosis, endoplasmic reticulum stress, autophagy, necroptosis and others has opened new possibilities for targeted interference with these pathways. While conventional chemotherapeutic agents usually inhibit cell cycle progression, DNA replication or mitosis execution, novel agents like small molecule kinase inhibitors also target survival-related kinases and signaling pathways and contribute to overcome resistance to chemotherapy and apoptosis. Additionally, antibodies targeting cellular death receptors have been described to specifically target tumor cells only. This review briefly highlights the pathways involved in (apoptotic) cell death and summarizes the current state of development of specific modulators of cell death and how they can help to improve the tolerability of chemotherapy regimens and increase survival rates in patients with advanced cancer diseases.

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“…Gossypol (also known as AT-101), a natural product found in cottonseed, is a nonselective inhibitor of LDH that blocks the binding of NADH, with a K i for LDHA and LDHB of 1.9 and 1.4 μM, respectively (50,51). This compound was initially developed as an antimalarial therapeutic, but is now being used in Phase I and Phase II clinical oncology trials (52)(53)(54). However, gossypol also inhibits GAPDH, which is an NAD + -dependent enzyme, and thus its antitumor activity may also include the inhibition of GAPDH.…”

Section: Ldha Inhibitors As Cancer Therapeuticsmentioning

confidence: 99%

Targeting lactate metabolism for cancer therapeutics

Doherty¹,

Cleveland²

2013

J. Clin. Invest.

920

876

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Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

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Phase I/II Study of AT-101 with Topotecan in Relapsed and Refractory Small Cell Lung Cancer

Cited by 77 publications

References 25 publications

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

Apoptosis-Modulating Drugs for Improved Cancer Therapy

Targeting lactate metabolism for cancer therapeutics

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