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PMC:7696151 / 72694-86809 JSONTXT

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LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
2157 809-813 Gene denotes P-gp Gene:283871
2158 815-820 Gene denotes ABCB1 Gene:5243
2159 1605-1609 Gene denotes KRAS Gene:16653
2160 1635-1638 Gene denotes p53 Gene:22060
2161 1782-1785 Gene denotes p53 Gene:22060
2162 1949-1952 Gene denotes p53 Gene:22060
2163 1978-1981 Gene denotes p53 Gene:22060
2164 2402-2405 Gene denotes p53 Gene:22060
2165 2567-2570 Gene denotes p53 Gene:22060
2166 2639-2643 Gene denotes KRAS Gene:16653
2167 1433-1439 Species denotes murine Tax:10090
2168 1569-1573 Species denotes Mice Tax:10090
2169 2609-2613 Species denotes mice Tax:10090
2170 18-21 Chemical denotes HCQ MESH:D006886
2171 98-101 Chemical denotes HCQ MESH:D006886
2172 764-767 Chemical denotes HCQ MESH:D006886
2173 1165-1168 Chemical denotes HCQ MESH:D006886
2174 1714-1717 Chemical denotes HCQ MESH:D006886
2175 1818-1821 Chemical denotes HCQ MESH:D006886
2176 2170-2173 Chemical denotes HCQ MESH:D006886
2177 2299-2302 Chemical denotes HCQ MESH:D006886
2178 2800-2810 Chemical denotes trametinib MESH:C560077
2179 2971-2974 Chemical denotes HCQ MESH:D006886
2180 2998-3008 Chemical denotes trametinib MESH:C560077
2181 180-186 Disease denotes tumors MESH:D009369
2182 543-549 Disease denotes cancer MESH:D009369
2183 899-911 Disease denotes cytotoxicity MESH:D064420
2184 915-933 Disease denotes refractory cancers MESH:D009369
2185 1009-1015 Disease denotes cancer MESH:D009369
2186 1061-1066 Disease denotes tumor MESH:D009369
2187 1383-1388 Disease denotes tumor MESH:D009369
2188 1450-1482 Disease denotes pancreatic ductal adenocarcinoma MESH:D021441
2189 1494-1500 Disease denotes cancer MESH:D009369
2190 1513-1522 Disease denotes mortality MESH:D003643
2191 1691-1696 Disease denotes tumor MESH:D009369
2192 1836-1841 Disease denotes tumor MESH:D009369
2193 2002-2008 Disease denotes cancer MESH:D009369
2194 2060-2093 Disease denotes pancreatic ductal adenocarcinomas MESH:D021441
2195 2185-2190 Disease denotes tumor MESH:D009369
2196 2341-2373 Disease denotes pancreatic ductal adenocarcinoma MESH:D021441
2197 2711-2736 Disease denotes pancreatic carcinogenesis MESH:D063646
2198 3054-3079 Disease denotes reduction of tumor lesion MESH:D051437
2199 3098-3103 Disease denotes tumor MESH:D009369
2200 3116-3122 Disease denotes cancer MESH:D009369
2201 3134-3138 Disease denotes pain MESH:D010146
2242 3962-3979 Gene denotes estrogen receptor Gene:2099
2243 3195-3200 Species denotes human Tax:9606
2244 4131-4135 Species denotes mice Tax:10090
2245 4222-4226 Species denotes mice Tax:10090
2246 3261-3264 Chemical denotes HCQ MESH:D006886
2247 3525-3528 Chemical denotes HCQ MESH:D006886
2248 3562-3572 Chemical denotes Epirubicin MESH:D015251
2249 3792-3795 Chemical denotes HCQ MESH:D006886
2250 4043-4052 Chemical denotes tamoxifen MESH:D013629
2251 4115-4118 Chemical denotes HCQ MESH:D006886
2252 4148-4153 Chemical denotes water MESH:D014867
2253 4202-4211 Chemical denotes tamoxifen MESH:D013629
2254 4267-4270 Chemical denotes HCQ MESH:D006886
2255 4384-4387 Chemical denotes HCQ MESH:D006886
2256 4417-4428 Chemical denotes vemurafenib MESH:D000077484
2257 4533-4536 Chemical denotes HCQ MESH:D006886
2258 4552-4559 Chemical denotes CCI-779 MESH:C401859
2259 4736-4739 Chemical denotes HCQ MESH:D006886
2260 4979-4982 Chemical denotes HCQ MESH:D006886
2261 3149-3155 Disease denotes cancer MESH:D009369
2262 3171-3178 Disease denotes ovarian MESH:D010049
2263 3201-3214 Disease denotes breast cancer MESH:D001943
2264 3283-3288 Disease denotes tumor MESH:D009369
2265 3444-3450 Disease denotes cancer MESH:D009369
2266 3532-3538 Disease denotes cancer MESH:D009369
2267 3592-3605 Disease denotes breast cancer MESH:D001943
2268 3749-3755 Disease denotes cancer MESH:D009369
2269 3884-3889 Disease denotes tumor MESH:D009369
2270 3989-4003 Disease denotes breast cancers MESH:D001943
2271 4186-4192 Disease denotes cancer MESH:D009369
2272 4256-4265 Disease denotes carcinoma MESH:D009369
2273 4345-4350 Disease denotes tumor MESH:D009369
2274 4643-4657 Disease denotes melanoma tumor MESH:D008545
2275 4678-4683 Disease denotes tumor MESH:D009369
2276 4779-4805 Disease denotes chemoresistant lung cancer MESH:D008175
2277 4823-4829 Disease denotes cancer MESH:D009369
2278 4835-4842 Disease denotes hypoxic MESH:D000860
2279 4886-4892 Disease denotes cancer MESH:D009369
2280 5045-5050 Disease denotes tumor MESH:D009369
2281 5140-5145 Disease denotes tumor MESH:D009369
2289 5445-5449 Species denotes mice Tax:10090
2290 5488-5491 Chemical denotes HCQ MESH:D006886
2291 5541-5556 Chemical denotes 3-bromopyruvate MESH:C017092
2292 5334-5340 Disease denotes cancer MESH:D009369
2293 5420-5436 Disease denotes ascites hepatoma MESH:D001201
2294 5591-5596 Disease denotes tumor MESH:D009369
2295 5748-5754 Disease denotes cancer MESH:D009369
2380 5881-5886 Gene denotes Bcl-2 Gene:596
2381 5891-5897 Gene denotes Bcl-xL Gene:598
2382 6343-6348 Gene denotes Bcl-2 Gene:12043
2383 6688-6704 Gene denotes interferon-alpha Gene:111654
2384 6896-6912 Gene denotes interferon-alpha Gene:111654
2385 7065-7081 Gene denotes interferon-alpha Gene:111654
2386 7982-7990 Gene denotes Beclin 1 Gene:56208
2387 9391-9394 Gene denotes CA4 Gene:12351
2388 9535-9538 Gene denotes CA4 Gene:12351
2389 10209-10213 Gene denotes IL-6 Gene:3569
2390 9341-9344 Gene denotes CA4 Gene:12351
2391 6126-6130 Species denotes mice Tax:10090
2392 6443-6447 Species denotes mice Tax:10090
2393 6557-6561 Species denotes mice Tax:10090
2394 7002-7006 Species denotes mice Tax:10090
2395 7382-7387 Species denotes mouse Tax:10090
2396 8021-8027 Species denotes murine Tax:10090
2397 8549-8555 Species denotes humans Tax:9606
2398 8752-8757 Species denotes human Tax:9606
2399 8758-8763 Species denotes mouse Tax:10090
2400 8900-8904 Species denotes mice Tax:10090
2401 9505-9509 Species denotes mice Tax:10090
2402 10618-10626 Species denotes patients Tax:9606
2403 6021-6024 Chemical denotes HCQ MESH:D006886
2404 6069-6076 Chemical denotes ABT-737 MESH:C501332
2405 6229-6232 Chemical denotes HCQ MESH:D006886
2406 6236-6243 Chemical denotes ABT-737 MESH:C501332
2407 6385-6388 Chemical denotes HCQ MESH:D006886
2408 7087-7090 Chemical denotes HCQ MESH:D006886
2409 7115-7125 Chemical denotes wortmannin MESH:D000077191
2410 7283-7286 Chemical denotes HCQ MESH:D006886
2411 7338-7347 Chemical denotes melatonin MESH:D008550
2412 7423-7432 Chemical denotes melatonin MESH:D008550
2413 7620-7623 Chemical denotes HCQ MESH:D006886
2414 7642-7651 Chemical denotes melatonin MESH:D008550
2415 8003-8006 Chemical denotes HCQ MESH:D006886
2416 8319-8322 Chemical denotes HCQ MESH:D006886
2417 8343-8346 Chemical denotes HCQ MESH:D006886
2418 8471-8474 Chemical denotes HCQ MESH:D006886
2419 8582-8585 Chemical denotes HCQ MESH:D006886
2420 8649-8661 Chemical denotes chlorambucil MESH:D002699
2421 8848-8851 Chemical denotes HCQ MESH:D006886
2422 8856-8868 Chemical denotes chlorambucil MESH:D002699
2423 9051-9054 Chemical denotes HCQ MESH:D006886
2424 9139-9142 Chemical denotes HCQ MESH:D006886
2425 9245-9256 Chemical denotes doxorubicin MESH:D004317
2426 9421-9424 Chemical denotes HCQ MESH:D006886
2427 9674-9677 Chemical denotes HCQ MESH:D006886
2428 9702-9706 Chemical denotes iron MESH:D007501
2429 9717-9720 Chemical denotes ROS MESH:D017382
2430 10137-10140 Chemical denotes HCQ MESH:D006886
2431 10358-10368 Chemical denotes paclitaxel MESH:D017239
2432 10447-10450 Chemical denotes HCQ MESH:D006886
2433 10506-10509 Chemical denotes HCQ MESH:D006886
2434 5859-5874 Disease denotes β-Cell Lymphoma MESH:D016399
2435 6099-6115 Disease denotes prostatic cancer MESH:D011471
2436 6421-6434 Disease denotes neuroblastoma MESH:D009447
2437 6494-6499 Disease denotes tumor MESH:D009369
2438 6533-6543 Disease denotes metastases MESH:D009362
2439 6714-6720 Disease denotes cancer MESH:D009369
2440 7021-7044 Disease denotes neck squamous carcinoma MESH:D000077195
2441 7175-7180 Disease denotes tumor MESH:D009369
2442 7358-7381 Disease denotes squamous cell carcinoma MESH:D002294
2443 7696-7701 Disease denotes tumor MESH:D009369
2444 7760-7765 Disease denotes tumor MESH:D009369
2445 8038-8051 Disease denotes breast cancer MESH:D001943
2446 8306-8317 Disease denotes tumor death MESH:D003643
2447 8716-8740 Disease denotes leukemia/lymphoma cancer MESH:D009369
2448 8773-8791 Disease denotes Burkitt’s lymphoma MESH:D002051
2449 8977-8985 Disease denotes toxicity MESH:D064420
2450 9152-9157 Disease denotes tumor MESH:D009369
2451 9277-9285 Disease denotes melanoma MESH:D008545
2452 9439-9444 Disease denotes tumor MESH:D009369
2453 9490-9501 Disease denotes lung cancer MESH:D008175
2454 9661-9666 Disease denotes tumor MESH:D009369
2455 9839-9856 Disease denotes pancreatic cancer MESH:D010190
2456 10070-10086 Disease denotes liver metastases MESH:D009362
2457 10260-10266 Disease denotes cancer MESH:D009369
2458 10332-10347 Disease denotes stroma fibrosis MESH:D005355
2459 10389-10394 Disease denotes tumor MESH:D009369
2460 10463-10480 Disease denotes pancreatic cancer MESH:D010190
2461 10659-10676 Disease denotes pancreatic cancer MESH:D010190
2462 10713-10732 Disease denotes progressive disease MESH:D018450
2463 9485-9489 CellLine denotes A549 CVCL:0023
2474 11303-11307 Species denotes mice Tax:10090
2475 10987-10990 Chemical denotes HCQ MESH:D006886
2476 11183-11186 Chemical denotes HCQ MESH:D006886
2477 11221-11227 Chemical denotes ZD6474 MESH:C452423
2478 11342-11348 Chemical denotes ZD6474 MESH:C452423
2479 11443-11446 Chemical denotes HCQ MESH:D006886
2480 10899-10904 Disease denotes tumor MESH:D009369
2481 11052-11064 Disease denotes brain tumors MESH:D001932
2482 11288-11294 Disease denotes glioma MESH:D005910
2483 11496-11502 Disease denotes glioma MESH:D005910
2531 11643-11651 Species denotes patients Tax:9606
2532 11999-12006 Species denotes patient Tax:9606
2533 12252-12256 Species denotes mice Tax:10090
2534 12487-12495 Species denotes patients Tax:9606
2535 12799-12807 Species denotes patients Tax:9606
2536 12942-12950 Species denotes Patients Tax:9606
2537 13247-13255 Species denotes patients Tax:9606
2538 13374-13382 Species denotes patients Tax:9606
2539 14020-14028 Species denotes patients Tax:9606
2540 14100-14108 Species denotes patients Tax:9606
2541 11550-11553 Chemical denotes HCQ MESH:D006886
2542 11667-11679 Chemical denotes temozolomide MESH:D000077204
2543 11921-11924 Chemical denotes HCQ MESH:D006886
2544 12144-12147 Chemical denotes HCQ MESH:D006886
2545 12279-12282 Chemical denotes HCQ MESH:D006886
2546 12382-12385 Chemical denotes HCQ MESH:D006886
2547 12596-12608 Chemical denotes temsirolimus MESH:C401859
2548 12630-12633 Chemical denotes HCQ MESH:D006886
2549 12740-12743 Chemical denotes HCQ MESH:D006886
2550 12877-12889 Chemical denotes temozolomide MESH:D000077204
2551 12914-12917 Chemical denotes HCQ MESH:D006886
2552 13311-13314 Chemical denotes HCQ MESH:D006886
2553 13512-13515 Chemical denotes HCQ MESH:D006886
2554 13520-13530 Chemical denotes bortezomib MESH:D000069286
2555 13630-13633 Chemical denotes HCQ MESH:D006886
2556 13651-13661 Chemical denotes bortezomib MESH:D000069286
2557 13816-13819 Chemical denotes HCQ MESH:D006886
2558 13904-13914 Chemical denotes everolimus MESH:D000068338
2559 11630-11642 Disease denotes glioblastoma MESH:D005909
2560 11799-11804 Disease denotes tumor MESH:D009369
2561 11869-11877 Disease denotes toxicity MESH:D064420
2562 12042-12050 Disease denotes toxicity MESH:D064420
2563 12062-12078 Disease denotes myelosuppression MESH:D001855
2564 12080-12088 Disease denotes anorexia MESH:D000855
2565 12090-12097 Disease denotes fatigue MESH:D005221
2566 12102-12108 Disease denotes nausea MESH:D009325
2567 12507-12513 Disease denotes tumors MESH:D009369
2568 12528-12536 Disease denotes melanoma MESH:D008545
2569 12682-12687 Disease denotes tumor MESH:D009369
2570 12784-12792 Disease denotes toxicity MESH:D064420
2571 12824-12832 Disease denotes melanoma MESH:D008545
2572 13153-13163 Disease denotes toxicities MESH:D064420
2573 13261-13268 Disease denotes myeloma MESH:D009101
2574 13569-13576 Disease denotes myeloma MESH:D009101
2575 13767-13773 Disease denotes cancer MESH:D009369
2576 13856-13864 Disease denotes toxicity MESH:D064420
2577 13988-14019 Disease denotes clear-cell renal cell carcinoma MESH:C538614

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T135 543-549 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T136 632-647 Phenotype denotes drug resistance http://purl.obolibrary.org/obo/HP_0020174
T137 1009-1015 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T138 1061-1066 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T139 1383-1388 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T140 1494-1500 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T141 1691-1696 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T142 1836-1841 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T143 2002-2008 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T144 2185-2190 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T145 3067-3072 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T146 3098-3103 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T147 3116-3122 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T148 3134-3138 Phenotype denotes pain http://purl.obolibrary.org/obo/HP_0012531
T149 3149-3155 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T150 3201-3214 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T151 3283-3288 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T152 3444-3450 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T153 3532-3538 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T154 3592-3605 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T155 3749-3755 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T156 3884-3889 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T157 3989-4003 Phenotype denotes breast cancers http://purl.obolibrary.org/obo/HP_0003002
T158 4186-4192 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T159 4256-4265 Phenotype denotes carcinoma http://purl.obolibrary.org/obo/HP_0030731
T160 4345-4350 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T161 4643-4651 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T162 4652-4657 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T163 4678-4683 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T164 4794-4805 Phenotype denotes lung cancer http://purl.obolibrary.org/obo/HP_0100526
T165 4823-4829 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T166 4886-4892 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T167 5045-5050 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T168 5140-5145 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T169 5334-5340 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T170 5420-5427 Phenotype denotes ascites http://purl.obolibrary.org/obo/HP_0001541
T171 5591-5596 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T172 5748-5754 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T173 5866-5874 Phenotype denotes Lymphoma http://purl.obolibrary.org/obo/HP_0002665
T174 6099-6115 Phenotype denotes prostatic cancer http://purl.obolibrary.org/obo/HP_0012125
T175 6144-6149 Phenotype denotes Tumor http://purl.obolibrary.org/obo/HP_0002664
T176 6421-6434 Phenotype denotes neuroblastoma http://purl.obolibrary.org/obo/HP_0003006
T177 6494-6499 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T178 6714-6720 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T179 7035-7044 Phenotype denotes carcinoma http://purl.obolibrary.org/obo/HP_0030731
T180 7175-7180 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T181 7358-7381 Phenotype denotes squamous cell carcinoma http://purl.obolibrary.org/obo/HP_0002860
T182 7696-7701 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T183 7760-7765 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T184 8038-8051 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T185 8306-8311 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T186 8716-8724 Phenotype denotes leukemia http://purl.obolibrary.org/obo/HP_0001909
T187 8725-8733 Phenotype denotes lymphoma http://purl.obolibrary.org/obo/HP_0002665
T188 8734-8740 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T189 8773-8791 Phenotype denotes Burkitt’s lymphoma http://purl.obolibrary.org/obo/HP_0030080
T190 9152-9157 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T191 9277-9285 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T192 9439-9444 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T193 9490-9501 Phenotype denotes lung cancer http://purl.obolibrary.org/obo/HP_0100526
T194 9661-9666 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T195 9839-9856 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T196 10028-10033 Phenotype denotes Tumor http://purl.obolibrary.org/obo/HP_0002664
T197 10260-10266 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T198 10389-10394 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T199 10463-10480 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T200 10659-10676 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T201 10899-10904 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T202 11052-11064 Phenotype denotes brain tumors http://purl.obolibrary.org/obo/HP_0030692
T203 11288-11294 Phenotype denotes glioma http://purl.obolibrary.org/obo/HP_0009733
T204 11496-11502 Phenotype denotes glioma http://purl.obolibrary.org/obo/HP_0009733
T205 11630-11642 Phenotype denotes glioblastoma http://purl.obolibrary.org/obo/HP_0012174
T206 11799-11804 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T207 12080-12088 Phenotype denotes anorexia http://purl.obolibrary.org/obo/HP_0002039
T208 12090-12097 Phenotype denotes fatigue http://purl.obolibrary.org/obo/HP_0012378
T209 12102-12108 Phenotype denotes nausea http://purl.obolibrary.org/obo/HP_0002018
T210 12528-12536 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T211 12682-12687 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T212 12824-12832 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T213 13744-13763 Phenotype denotes autophagic vacuoles http://purl.obolibrary.org/obo/HP_0003736
T214 13767-13773 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T215 13988-14019 Phenotype denotes clear-cell renal cell carcinoma http://purl.obolibrary.org/obo/HP_0006770

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T463 0-6 Sentence denotes 2.4.3.
T464 7-17 Sentence denotes Anticancer
T465 18-97 Sentence denotes HCQ explains its antitumor activity thanks to its ability to inhibit autophagy.
T466 98-162 Sentence denotes HCQ is, indeed, an FDA-approved drug inhibiting autophagy [135].
T467 163-240 Sentence denotes Several types of tumors develop chemoresistance by enhancing autophagic flux.
T468 241-423 Sentence denotes Autophagy consists in the sequestration of materials in autophagic vesicles to be eliminated through lysosomal fusion and allows cells to overcome metabolic and therapeutic stresses.
T469 424-526 Sentence denotes By recycling intracellular components, cells may maintain an energy balance and increase their growth.
T470 527-593 Sentence denotes If it occurs in cancer cells, resistance mechanisms may establish.
T471 594-737 Sentence denotes One of the mechanisms responsible for drug resistance is related to increased drug efflux by ATP-binding cassette (ABC) transporters [136,137].
T472 738-974 Sentence denotes It has been observed that HCQ is significantly reduced the increase in P-gp (ABCB1) expression and, in combination with several anticancer drugs, induced higher cytotoxicity in refractory cancers by inhibiting autophagic activity [138].
T473 975-1091 Sentence denotes However, the role of autophagy in cancer is controversial and depends on genotype and tumor stage development [139].
T474 1092-1289 Sentence denotes Many clinical trials examined the synergistic effects of the addition of HCQ to conventional chemotherapic drugs, finding that the role of autophagy is complex and is influenced by several factors.
T475 1290-1407 Sentence denotes Depending on genetic concomitant alterations, autophagy may possess both pro-tumorigenic and tumor-suppressive roles.
T476 1408-1568 Sentence denotes It has been confirmed in murine models of pancreatic ductal adenocarcinoma, a type of cancer with a high mortality rate, due to its refractoriness to therapies.
T477 1569-1738 Sentence denotes Mice presenting activated oncogenic KRAS and normal expression of p53 oncosuppressor experienced a critical regression of tumor developing under HCQ (60 mg/kg/day i.p.).
T478 1739-1959 Sentence denotes By contrast, in those with a deficiency of p53, the inhibition of autophagy by HCQ increased the tumor progression, demonstrating that autophagy’s role in tumorigenesis is strictly related to the expression of p53 [140].
T479 1960-2100 Sentence denotes The expression of p53 is often altered in cancer, so as to be found mutated or absent in the 75% of pancreatic ductal adenocarcinomas [141].
T480 2101-2197 Sentence denotes This issue highlights the necessity to carefully evaluate the use of HCQ in certain tumor types.
T481 2198-2423 Sentence denotes Different outcomes have been previously described, it has been found that inhibition of autophagy by HCQ might arise as a valuable adjuvant in pancreatic ductal adenocarcinoma chemotherapy, regardless of p53 status [142,143].
T482 2424-2628 Sentence denotes Given the same doses and route of administration, these inconsistencies between the two reported studies could probably derive from the use of p53 homozygous and heterozygous models of mice, respectively.
T483 2629-2737 Sentence denotes Regarding KRAS oncoprotein, its downstream pathway is one of the major players of pancreatic carcinogenesis.
T484 2738-2862 Sentence denotes The inhibition of this pathway by cytotoxic drugs, as well as trametinib, is often associated with an increase in autophagy.
T485 2863-3139 Sentence denotes For this reason, Drucker and Rosen [144] performed an off-label trial with an association of 400–1200 mg of HCQ and a constant dose of trametinib, observing a partial response with a general reduction of tumor lesion size, circulating tumor markers and cancer-associated pain.
T486 3140-3295 Sentence denotes In other cancer types, such as ovarian, prostatic, and human breast cancer, the anticancer or pro-tumorigenic effects of HCQ are determined by tumor stage.
T487 3296-3466 Sentence denotes In the early stages of the disease, the inhibition of autophagy results in an inhibition of tumorigenesis, while in the advanced phase, it enhances cancer survival [145].
T488 3467-3561 Sentence denotes Then, it is important in assessing the contextual role of HCQ in cancer resistance mechanisms.
T489 3562-3668 Sentence denotes Epirubicin in triple-negative breast cancer therapy often lost efficacy, due to chemoresistance acquiring.
T490 3669-3770 Sentence denotes It has been shown that this cytotoxic agent induced autophagic flux, increasing cancer cell survival.
T491 3771-3948 Sentence denotes The combination with HCQ (120 mg/kg by i.p.), thanks to the anti-autophagic properties, significantly suppressed tumor growth by up to 50% with respect to the monotherapy [142].
T492 3949-4090 Sentence denotes In addition, estrogen receptor-positive breast cancers developed resistance to treatment with tamoxifen, due to the enhancement of autophagy.
T493 4091-4218 Sentence denotes The coadministration of HCQ (1–2 mg/day/mice in drinking water) restored the susceptibility of cancer cells to tamoxifen [146].
T494 4219-4487 Sentence denotes In mice with thyroid gland xenograft carcinoma, HCQ (150 mg/kg/day p.o. for two weeks) did not provide significant results on tumor growth, while the combination of HCQ with the chemotherapic agent vemurafenib potentiated the anticancer properties of both drugs [147].
T495 4488-4735 Sentence denotes Similarly, the two weeks coadministration of HCQ (65 mg/kg) and CCI-779 resulted in a synergism that significantly enhanced their in vivo activity against melanoma tumor growth, in terms of tumor size, with respect to their single treatment [148].
T496 4736-4806 Sentence denotes HCQ was revealed also to be active against chemoresistant lung cancer.
T497 4807-4978 Sentence denotes In this type of cancer, the hypoxic conditions led to lesser susceptibility of cancer cells towards lymphocyte T-mediated cytolysis, thanks to the activation of autophagy.
T498 4979-5152 Sentence denotes HCQ intake, at doses of 30 mg/kg/day i.p. for 10 days, sensitized tumor cells to lysis and allowed, together with conventional treatment, the eradication of the tumor [149].
T499 5153-5255 Sentence denotes Together with autophagy, glycolysis plays a pivotal role in satisfying the increased energetic demand.
T500 5256-5347 Sentence denotes The dual targeting of the processes may provide a new therapeutic approach in cancer cells.
T501 5348-5615 Sentence denotes Emonet, et al. [150] performed a randomized preclinical study on Earlic ascites hepatoma-bearing mice, showing that the coadministration of HCQ (60 mg/kg i.p.) and the antiglycolytic inhibitor 3-bromopyruvate possessed a synergistic effect on tumor growth inhibition.
T502 5616-5807 Sentence denotes Moreover, this treatment is associated with an improvement of oxidative status in hepatic tissue, with a decrement in the number of cancer cells, without affecting the total cell count [151].
T503 5808-5933 Sentence denotes Resistance mechanisms also involved alterations in β-Cell Lymphoma (Bcl) Bcl-2 and Bcl-xL and anti-apoptotic gene expression.
T504 5934-6143 Sentence denotes To evaluate the validity of the dual approach, targeting both apoptosis and autophagy, HCQ (50 mg/kg i.p.) and an apoptosis inhibitor, ABT-737, were administered to prostatic cancer xenograft mice for 15 days.
T505 6144-6256 Sentence denotes Tumor growth was significantly suppressed by a combination of drugs, with respect to HCQ or ABT-737 alone [152].
T506 6257-6448 Sentence denotes In the same way, Fenollar, et al. [153] demonstrated the efficacy of Obatoclax, a pan-Bcl-2 inhibitor, used in association with HCQ (3–60 mg/kg) or conventional in neuroblastoma-bearing mice.
T507 6449-6627 Sentence denotes Positive outcomes regarded the diminution of tumor size and the complete absence of metastases in cotreated mice with respect to Obatoclax alone or with respect to control [154].
T508 6628-6783 Sentence denotes Apoptosis is also at the base of the anticancer activity of interferon-alpha, but the cancer treatment with this drug alone often leads to chemoresistance.
T509 6784-6985 Sentence denotes It has been demonstrated that autophagy is in the main responsible for chemoresistance, thus the combination of interferon-alpha with inhibitors of autophagic flux may be a useful therapeutic approach.
T510 6986-7194 Sentence denotes In 30 xenograft mice with head and neck squamous carcinoma, the combination of interferon-alpha with HCQ (60 mg/kg/day i.g.) and wortmannin synergistically promoted apoptosis and inhibited tumor growth [155].
T511 7195-7395 Sentence denotes In a similar fashion, Le Goff, et al. [156] investigated the potential synergic role of HCQ (30 mg/kg) in enhancing the anticancer activity of melatonin on tongue squamous cell carcinoma mouse models.
T512 7396-7470 Sentence denotes The anticancer activity of melatonin depends on its pro-apoptotic effects.
T513 7471-7571 Sentence denotes Nevertheless, this activity is accompanied by a pro-autophagic activity that caused chemoresistance.
T514 7572-7718 Sentence denotes The coadministration of the autophagy inhibitor HCQ strongly enhanced melatonin anticancer efficacy, resulting in a smaller tumor size and weight.
T515 7719-7882 Sentence denotes The effect of inhibition of autophagy on tumor growth may be enhanced if the inhibition of autophagic flux occurs when the process of autophagy is quite completed.
T516 7883-8052 Sentence denotes This hypothesis has been evaluated by Brönnimann, et al. [157], administering by intravenously TAT–Beclin 1 peptide and HCQ (65 mg/kg) in murine models of breast cancer.
T517 8053-8318 Sentence denotes Initially, the first agent induced the autophagic flux with the production of autophagosomes, while in the final phase of the process, the second stopped the autophagy by deacidification of lysosomes, causing the accumulation of autophagic vesicles and tumor death.
T518 8319-8417 Sentence denotes HCQ was administered as HCQ-loaded liposomes, to modulate the onset of autophagy inhibition [158].
T519 8418-8556 Sentence denotes This formulation allows us to overcome the limits of HCQ usage, related to the high doses required, which is often unachievable in humans.
T520 8557-8792 Sentence denotes Relatively high doses of HCQ were loaded in nanoparticles, together with the cytotoxic drug chlorambucil, demonstrating it to be safe and efficient in killing leukemia/lymphoma cancer cells in a human-mouse model of Burkitt’s lymphoma.
T521 8793-8905 Sentence denotes Eight injections of nanoparticles containing 400 mg of HCQ and chlorambucil led to the overall survival of mice.
T522 8906-8992 Sentence denotes These concentrations of free drugs are inapplicable, due to their high toxicity [159].
T523 8993-9286 Sentence denotes As demonstrated by Naso, Wong, Wong, Chen and Hoang [72], HCQ liposomes (60 mg/kg), together with a pH-sensitive targeting peptide that delivered HCQ into the tumor cells and lysosomes, enhanced the chemotherapic effect of conventional anticancer drug doxorubicin in animal models of melanoma.
T524 9287-9510 Sentence denotes Likewise, Vayssade, et al. [160] conceived a nanogel (CA4-FeAlg/HCQ) for co-addressing vascular blocker CA4 and anti-autophagic agent HCQ (30 mg/kg) in tumor blood vessels, to synergistically treat A549 lung cancer in mice.
T525 9511-9760 Sentence denotes Firstly, the release of CA4 exerted anti-angiogenic effects in the vascular site, then FeAlg/HCQ were released into small nanogels and entered in the tumor, where HCQ inhibited autophagy and iron generated ROS with a synergic antitumor effect [161].
T526 9761-10027 Sentence denotes Similarly, De Jong, et al. [162] evaluated the response of an animal model of pancreatic cancer to HCQ (5 mg/kg) and paclitaxel administration, loaded in liposomes, modified with an acid environmental sensitive peptide that is responsible for site-specific delivery.
T527 10028-10114 Sentence denotes Tumor weight, together with the number of liver metastases, was significantly reduced.
T528 10115-10289 Sentence denotes The administration of HCQ is associated with the inhibition of autophagy and the reduction of IL-6 that is responsible for cross-talking between cancer cells and fibroblasts.
T529 10290-10406 Sentence denotes All these events avoided the formation of stroma fibrosis, allowing paclitaxel to easily reach the tumor site [104].
T530 10407-10481 Sentence denotes The synergism results are essential for HCQ activity in pancreatic cancer.
T531 10482-10566 Sentence denotes In monotherapy, indeed, HCQ (800–1200 mg/day) did not achieve significant autophagy.
T532 10567-10767 Sentence denotes This resulted in negligible therapeutic effects in patients with already-treated metastatic pancreatic cancer, of which only 10% were without the progressive disease after two months of therapy [163].
T533 10768-10956 Sentence denotes Therefore, the use of modified formulations, such as liposomes, nanogels, etc., may be a precious tools for drug codelivery at the tumor site, enhancing efficacy and reducing side effects.
T534 10957-11158 Sentence denotes Moreover, the availability of HCQ in those formulations encouraged the use of this molecule in brain tumors, as this formulation highly improved the penetration of this drug in the brain–blood barrier.
T535 11159-11349 Sentence denotes The co-encapsulation of HCQ with a tyrosine kinase inhibitor, ZD6474, exhibited a synergistic effect, increasing the survival of glioma-bearing mice by two-times with respect to free ZD6474.
T536 11350-11519 Sentence denotes Those synergistic effects are attributable to significant inhibition of autophagy exerted by HCQ and might provide a valuable therapeutic tool in glioma treatment [164].
T537 11520-11703 Sentence denotes The anticancer effect of free HCQ at 200–800 mg/day p.o. has been evaluated in two similar clinical trials on glioblastoma patients in concomitant temozolomide drugs and radiotherapy.
T538 11704-11935 Sentence denotes Although a dose-dependent significant increase of autophagy markers, no significant effects on tumor suppression were recorded in both studies, as the dose-limiting toxicity was not allowed to achieve higher doses of HCQ [162,165].
T539 11936-12109 Sentence denotes The maximum tolerated dose is the dose over which at least one patient from six experienced dose-limiting toxicity, including myelosuppression, anorexia, fatigue, or nausea.
T540 12110-12294 Sentence denotes Moreover, it has been proved that HCQ severely altered the organization of the Golgi apparatus and the endolysosomal system in C57BL/6JolaHsd mice under 60 mg/kg/day of HCQ i.p. [166].
T541 12295-12547 Sentence denotes However, different from Rosenfeld’s studies, no maximum tolerated dose was reached for HCQ in combination with chemotherapic temsirolimus, allowing us to perform a dose-escalation study on 27 patients with solid tumors and 12 with a melanoma diagnosis.
T542 12548-12701 Sentence denotes In both cases, the standard intravenous dose of temsirolimus with 1200 mg of oral HCQ was considered safe and tolerated and inhibited tumor growth [167].
T543 12702-12941 Sentence denotes The same authors further assessed the HCQ anticancer properties and dose-limiting toxicity on 40 patients with metastatic melanoma, by administering a dose intense regimen of temozolomide and escalating doses of HCQ (200–1200 mg/day p.o.).
T544 12942-13097 Sentence denotes Patients well tolerated the treatment, showing a positive response in the 14% of cases and stability of disease in 27%, due to the modulation of autophagy.
T545 13098-13186 Sentence denotes No maximum tolerated dose was reached, although common toxicities were manifested [168].
T546 13187-13358 Sentence denotes According to the results of Rangwala, a phase I trial on 25 patients with myeloma demonstrated that the recommended dose of HCQ for a phase II trial is 600 mg twice a day.
T547 13359-13545 Sentence denotes Among eligible patients, 14% experienced a very good response, 14% minor responses, and 45% a period of stability in the disease when the association of HCQ and bortezomib were provided.
T548 13546-13786 Sentence denotes The synergic effect on myeloma was probably due to the combination of inhibition of HCQ on autophagy and bortezomib on proteasomal degradation, leading to the accumulation of misfolded proteins and autophagic vacuoles in cancer cells [169].
T549 13787-14115 Sentence denotes Likewise, doses of 600 mg of HCQ twice a day are not associated with toxicity and its usage as adjuvant therapy with everolimus was well tolerated and produced disease control in 67% of the metastatic clear-cell renal cell carcinoma patients and achieved the rate of six month progression-free survival in 45% of patients [170].