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Ref Type Journal Article
PMID (24548894)
Authors Zhang X, Fryknäs M, Hernlund E, Fayad W, De Milito A, Olofsson MH, Gogvadze V, Dang L, Påhlman S, Schughart LA, Rickardson L, D'Arcy P, Gullbo J, Nygren P, Larsson R, Linder S
Title Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments.
Journal Nature communications
Vol 5
Issue
Date 2014
URL
Abstract Text Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
VLX600 VLX-600|VLX 600 VLX600 is a small molecule drug that inhibits mitochondrial oxidative phosphorylation, which impairs mitochondrial function and induces autophagy, potentially increasing cell death, and inhibiting proliferation, and tumor growth (PMID: 24548894).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon carcinoma not applicable Oxaliplatin + VLX600 Preclinical - Cell culture Actionable In a preclinical study, VLX600 combined with Eloxatin (oxaliplatin) synergistically inhibited viability of colon carcinoma cells in culture (PMID: 24548894). 24548894
Unknown unknown breast carcinoma not applicable VLX600 Preclinical - Cell culture Actionable In a preclinical study, VLX600 treatment inhibited proliferation of a mouse breast carcinoma cell line in culture (PMID: 24548894). 24548894
Unknown unknown melanoma not applicable VLX600 Preclinical - Cell culture Actionable In a preclinical study, VLX600 treatment inhibited proliferation of a mouse melanoma cell line in culture (PMID: 24548894). 24548894
Unknown unknown colon carcinoma not applicable Fluorouracil + VLX600 Preclinical - Cell culture Actionable In a preclinical study, VLX600 and Adrucil (fluorouracil) combination treatment inhibited viability of colon carcinoma cells in culture (PMID: 24548894). 24548894
Unknown unknown colon carcinoma not applicable Irinotecan + VLX600 Preclinical - Cell line xenograft Actionable In a preclinical study, VLX600 combined with Camptosar (irinotecan) synergistically inhibited viability of colon carcinoma cells in culture, and inhibited tumor growth in an orthotopic cell line xenograft model (PMID: 24548894). 24548894
Unknown unknown colorectal cancer not applicable VLX600 Preclinical - Patient cell culture Actionable In a preclinical study, VLX600 treatment inhibited proliferation of cells derived from colorectal cancer patients in culture (PMID: 24548894). 24548894
Unknown unknown colon carcinoma not applicable VLX600 Preclinical - Cell line xenograft Actionable In a preclinical study, VLX600 treatment induced mitochondrial dysfunction, led to autophagy induced cell death, reduced clonogenicity and viability of quiescent cells in a spheroid culture, and inhibited proliferation of colon carcinoma cells in culture, and inhibited tumor growth in cell line xenograft models (PMID: 24548894). 24548894