Carbon ion radiotherapy of human lung cancer attenuates HIF‐1 signaling and acts with considerably enhanced therapeutic efficiency

Abstract

Carbon ion irradiation is an emerging therapeutic option for various tumor entities. Radiation resistance of solid tumors toward photon irradiation is caused by attenuation of DNA damage in less oxygenated tumor areas and by increased hypoxia-inducible factor (HIF)-1 signaling. Carbon ion irradiation acts independently of oxygen; however, the role of HIF-1 is unclear. We analyzed the effect of HIF-1 signaling after carbon ions in comparison to photons by using biological equivalent radiation doses in a human non-small-cell cancer model. The studies were performed in cultured A549 and H1299 cell lines and in A549 xenografts. Knockdown of HIF-1α in vivo combined with photon irradiation delayed tumor growth (23 vs. 13 d; P<0.05). Photon irradiation induced HIF-1α and target genes, predominantly in oxygenated cells (1.6-fold; P<0.05), with subsequent enhanced tumor angiogenesis (1.7-fold; P<0.05). These effects were not observed after carbon ion irradiation. Micro-DNA array analysis indicated that photons, but not carbon ions, significantly induced components of the mTOR (mammalian target of rapamycin) pathway (gene set enrichment analysis; P<0.01) as relevant for HIF-1α induction. After carbon ion irradiation in vivo, we observed substantially decreased HIF-1α levels (8.9-fold; P<0.01) and drastically delayed tumor growth (P<0.01), an important finding that indicates a higher relative biological effectiveness (RBE) than anticipated from the cell survival data. Taken together, the evidence showed that carbon ions mediate an improved therapeutic effectiveness without tumor-promoting HIF-1 signaling.

Activation of Angiogenesis Differs Strongly Between Pulmonary Carcinoids and Neuroendocrine Carinomas and Is Crucial for Carcinoid Tumourgenesis

“…The polymorphisms of Hypoxia-inducible factor 1-alpha (HIF1A), have been associated with prognosis of early stage non-small-cell lung cancer patients after surgery 27. The HIF1A was observed to be attenuated by carbon ion radiotherapy, enhancing the therapeutic efficiency of treatment 28. The main antiangiogenic agent in the first line is bevacizumab, however; recently completed studies have investigated cediranib, sorafenib, motesanib, axitinib and the vascular disrupting agent vadimezan 29.…”

Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer

“…15 Despite mounting evidence implicates HIF-1a plays a major role in carcinogenesis and cancer development and progression, it has been regarded as "undruggable." 16,17 A number of gene-therapy approaches have been developed for various cancers. [18][19][20] HIF-1a is viewed as a viable prospective target for novel pharmacologic approaches to the clinical management of solid tumors as it is the major regulator of the hypoxic adaptive response.…”

MicroRNAs Expression in Triple Negative vs Non Triple Negative Breast Cancer in Tunisia: Interaction with Clinical Outcome

“…They are small, regulatory molecules, approximately 20–25 nucleotides in length belonging to the largest family of non-coding RNAs [14]. They have an important role in gene silencing by binding directly and specifically to mRNA molecules and inducing their degradation (perfect match) or a decrease in the rate of the protein translation (imperfect match) [15]. Some microRNAs are down-regulated in a number of different tumors and the re-introduction of these microRNAs has been shown to impair the viability of cancer cells, because of their function as tumor-suppressor genes with an anti-proliferative and pro-apoptotic activity role.…”