Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism

Hori, Kentaro

doi:10.1007/s10555-011-9333-9

Cited by 9 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has also been shown to induce vascular disruption in tumors (44). Furthermore, combretastatin A-4 and other derivatives indicated typical antitumor effects by irreversible stoppage of tumor tissue blood flow for tumors growing in various tissues, organs, and for metastases (45)(46)(47). Compared with combretastatin, the moguntinones lost the effect of tubulin depolymerization (6).…”

Section: Resultsmentioning

confidence: 99%

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Maderer

Plutizki

Kramb

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3b and mTOR downstream targets were inhibited with IC 50 values in the nanomolar range. GSK3b signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 mmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer. Mol Cancer Ther; 13(6); 1399-409. Ó2014 AACR.

show abstract

Section: Resultsmentioning

confidence: 99%

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Maderer

Plutizki

Kramb

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…In this context, CBT is currently undergoing several clinical trials by Mateon Therapeutics ® , Inc., NCI (National Cancer Institute), and the Leukemia and Lymphoma Society for leukemia, thyroid cancer, OC, gastrointestinal cancers, and other solid tumors (Table ). CBT showed excellent antiangiogenic activity in preclinical studies by interfering with microtubule dynamics .…”

Section: Targeting the Tumor Vasculature By Natural Compounds: Perspementioning

confidence: 99%

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

2018

View full text Add to dashboard Cite

The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real‐world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs.

show abstract

“…These compounds irreversibly interrupted tumor blood flow (TBF) at about one‐fifth of the maximum tolerated dose and induced necrosis in almost all tumor tissue areas . One combretastatin derivative, Cderiv (=AC7700 = ombrabulin), had particularly effective TBF interruption, but without the severe bone marrow toxicity or cumulative toxicity of cytotoxic anticancer drugs . Combretastatins have thus attracted attention as agents to be used to starve solid tumors.…”

mentioning

confidence: 99%

“…(9)(10)(11)(12)(13)(14) One combretastatin derivative, Cderiv (=AC7700 = ombrabulin), had particularly effective TBF interruption, but without the severe bone marrow toxicity or cumulative toxicity of cytotoxic anticancer drugs. (15) Combretastatins have thus attracted attention as agents to be used to starve solid tumors.However, despite combretastatins' strong destructive effects on tumors, cancer cells often regrow in tumor margins and form viable tumor rims (i.e., recurrences). (3,13,16) One common feature of VDAs is that a viable rim occurs in tumor margins after treatment.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prevention of cancer recurrence in tumor margins by stopping microcirculation in the tumor and tumor–host interface

et al. 2014

Self Cite

View full text Add to dashboard Cite

Combretastatins interrupt blood flow of solid tumor vascular networks and lead to necrosis by blocking nutrients. However, tumors recover from tumor blood flow interruption-induced damage and develop viable rims. To investigate why cancer recurs and its prevention, we used a combretastatin derivative, Cderiv (=AC7700), and analyzed changes in tumor–host interface (T-HI) vessels, which were closest to cancer cells in the tumor margin after tumor vessel disruption, and the microenvironment surrounding them. Treatment with Cderiv (10 mg/kg) interrupted tumor blood flow in all regions of LY80 (a variant of Yoshida sarcoma) tumor, but not T-HI vessel blood flow. The same Cderiv dose given 72 h after 5 Gy irradiation stopped T-HI vessel blood flow and prevented cancer recurrence. Treatment in the reverse order, however, did not affect T-HI vessel blood flow. The greatest difference between the two treatments was the occurrence of gradual T-HI edema with the former. Severe T-HI edema compressed T-HI blood vessels, so that circulation stopped. Thus, the distance between a tumor margin and its nearest functioning host vessel became much larger, and the tumor marginal region became a microenvironment that lacked a nutritional supply. Cancer cells in tumor margins received nutrients through two circulation routes: tumor vessels and T-HI vessels. Our starvation methods, which involved treatment with Cderiv 72 h after 5 Gy irradiation, blocked both circulation routes and may have great potential as a clinical strategy to prevent cancer recurrence.

show abstract

Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism

Cited by 9 publications

References 50 publications

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

Prevention of cancer recurrence in tumor margins by stopping microcirculation in the tumor and tumor–host interface

Contact Info

Product

Resources

About