Insulin-resistant conditions: A favorable milieu for aggressive drug-resistant malignancies.

摘要: Epidemiological studies suggest that the risk of several solid and haematological malignancies (i.e., pancreas, liver, breast colorectal carcinomas, male female genitourinary neoplasms non-Hodgkin’s lymphomas) is increased in insulin-resistant diabetic patients with a prevalence estimated to be 8-18%. However, correct assessment this needs take account series potential confounding factors, as conditions associated insulin resistance hyperinsulinemia physical inactivity, obesity, diabetes treatment types high-saturated-fat diet), which are also independent factors for cancer. Furthermore, cancer characterized by worst outcome compared non-diabetic depends on an cancer-site specific mortality, reaches statistical significance breast, endometrial cancers, reduced sensitivity anticancer therapies (1). It has been suggested major mechanism responsible diabetics poor prognosis insulin-resistance resulting hyperinsulinemia. Chronic hyperinsulinemia, indeed, favors initiation and/or progression due direct mitogenic activity epithelial cells its ability stimulate indirectly increasing levels other modulators proliferation, such insulin-like growth factor (IGF-1) sex hormones. In addition, expression IGF-1 receptors inability down-regulate these response Thus, lead abnormal activation receptor signaling tumors cells, potentially explaining influence tumor therapies. fact, strong PI3K/AKT MAPK pathways results cascade proliferative anti-apoptotic events favoring progression, drug patient’s (2). Noteworthy, same subsequent likely obesity metabolic syndrome (3). In issue, Chen et al. present study addresses role AKT pathway oxaliplatin antiproliferative human (4). The authors high extracellular environment significant inhibition cytotoxic activity, could mediated pathway. Of note, selective pharmacological PI3K re-establishment oxaliplatin-induced cytotoxicity. This highlights two issues may relevant future clinical management obesity-associated cancers: played resistance. The first issue perspective design novel strategies reduce improve agents diabetes-associated malignancies. Recently, metformin, biguanide derivative widely used first-line therapy diabetes, proposed agent. Metformin activator AMPK, kinase acting central regulator cellular energy-consuming processes. metformin-dependent AMPK leads reversal hyperglycemia, resistance, effects, demonstrated cell models. Metformin’s modulate signaling, inhibit mTOR pathway, interfere angiogenesis induce cycle arrest apoptotic death. enhancement chemotherapy-dependent cytotoxicity Extremely rescuing malignant inhibitory metformin pathways, leading inactivation survival drug-induced death These evidences supported epidemiological suggesting type 2 treated (5). Based rationale ongoing trials have designed investigate single agent or combination traditional chemotherapeutics. provide support favor evaluation patients. Finally, relevance inducing carcinoma emphasized study. Indeed, lines hypothesis tyrosine induction mechanisms apoptosis (6). perspective, platin derivatives (6), well mitochondrial our group (7). inhibitors aim re-sensitize cytotoxics some them under presented highlight milieu conditioning factor, reprogramming at transcriptional post-transcription escape from apoptosis, resistance.