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PMC:7696151 / 72694-86809 JSONTXT 3 Projects

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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].