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return kwic search for significant out of >500 occurrences
583352 occurrences (No.14 in the rank) during 5 years in the PubMed. [cache]

26) Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens.

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PMID:33990407 DOI:10.1124/molpharm.120.000223

2021 Molecular pharmacology

* Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells.

- Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.

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(1)20 increase	(21)5 and	(41)2 DDIs	(61)2 heterogeneity
(2)16 differences	(22)5 improvement	(42)2 adverse	(62)2 impacts
(3)15 difference	(23)5 results	(43)2 antioxidant	(63)2 impairment
(4)13 reduction	(24)5 risk	(44)2 at	(64)2 implications
(5)11 changes	(25)4 amount	(45)2 barriers	(65)2 increased
(6)10 association	(26)4 associations	(46)2 being	(66)2 induction
(7)10 improvements	(27)4 burden	(47)2 benefits	(67)2 interaction
(8)10 positive	(28)4 clinical	(48)2 cause	(68)2 loci
(9)10 role	(29)4 public	(49)2 challenges	(69)2 morbidity
(10)9 impact	(30)3 advances	(50)2 clusters	(70)2 number
(11)8 decrease	(31)3 as	(51)2 cognitive	(71)2 personal
(12)8 in	(32)3 evidence	(52)2 consequence	(72)2 portion
(13)7 null	(33)3 expression	(53)2 contribution	(73)2 relationship
(14)7 effect	(34)3 gaps	(54)2 correlation	(74)2 sequence
(15)6 effects	(35)3 health	(55)2 factor	(75)2 survival
(16)6 increases	(36)3 highly	(56)2 finding	(76)2 than
(17)6 progress	(37)3 inhibition	(57)2 findings	(77)2 therapeutic
(18)6 proportion	(38)3 interactions	(58)2 for	(78)2 trend
(19)6 reductions	(39)3 predictors	(59)2 fraction	(79)2 variation
(20)5 (p	(40)3 upregulation	(60)2 functional	(80)2 variations

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--- WordNet output for significant --- =>意義深い, 重大な, 意味のある, 意味ありげな, 重要な Overview of adj significant The adj significant has 4 senses (first 4 from tagged texts) 1. (18) significant, important -- (important in effect or meaning; "a significant change in tax laws"; "a significant change in the Constitution"; "a significant contribution"; "significant details"; "statistically significant") 2. (9) significant, substantial -- (fairly large; "won by a substantial margin") 3. (3) significant -- (too closely correlated to be attributed to chance and therefore indicating a systematic relation; "the interaction effect is significant at the .01 level"; "no significant difference was found") 4. (2) meaning, pregnant, significant -- (rich in significance or implication; "a meaning look") --- WordNet end ---