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Publications (10 of 152) Show all publications
Tabernero, J., Yoshino, T., Stintzing, S., de Gramont, A., Gibbs, P., Jonker, D. J., . . . Lenz, H.-J. (2024). A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial. Cancer Research Communications, 4(1), 28-37
Open this publication in new window or tab >>A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial
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2024 (English)In: Cancer Research Communications, E-ISSN 2767-9764, Vol. 4, no 1, p. 28-37Article in journal (Refereed) Published
Abstract [en]

Purpose:

Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin).

Experimental Design:

AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR).

Results:

Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin.

Conclusions:

The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes.

Significance:

This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2024
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-527983 (URN)10.1158/2767-9764.CRC-23-0361 (DOI)001209565400003 ()38059497 (PubMedID)
Available from: 2024-05-15 Created: 2024-05-15 Last updated: 2024-05-15Bibliographically approved
Selvin, T., Berglund, M., Lenhammar, L., Lindskog, M., Jarvius, M., Larsson, R., . . . Andersson, C. R. (2024). Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs: an in vitro assessment. BMC Pharmacology & Toxicology, 25(1), Article ID 25.
Open this publication in new window or tab >>Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs: an in vitro assessment
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2024 (English)In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 25, no 1, article id 25Article in journal (Refereed) Published
Abstract [en]

Background

It has become evident in the field of oncology that the outcome of medical treatment is influenced by the combined effect exerted on both cancer- and immune cells. Therefore, we evaluated potential immunological effects of 46 standard anticancer agents and 22 commonly administered concomitant non-cancer drugs.

Methods

We utilized a miniaturized in vitro model system comprised of fluorescently labeled human colon and lung cancer cell lines grown as monocultures and co-cultured with activated peripheral blood mononuclear cells (PBMCs). The Bliss Independence Model was then applied to detect antagonism and synergy between the drugs and activated immune cells.

Results

Among the standard anticancer agents, tyrosine kinase inhibitors (TKIs) stood out as the top inducers of both antagonism and synergy. Ruxolitinib and dasatinib emerged as the most notably antagonistic substances, exhibiting the lowest Bliss scores, whereas sorafenib was shown to synergize with activated PBMCs. Most concomitant drugs did not induce neither antagonism nor synergy. However, the statins mevastatin and simvastatin were uniquely shown to synergize with activated PBMC at all tested drug concentrations in the colon cancer model.

Conclusion

We utilized a miniaturized tumor-immune model to enable time and cost-effective evaluation of a broad panel of drugs in an immuno-oncology setting in vitro. Using this approach, immunomodulatory effects exerted by TKIs and statins were identified.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Anticancer drugs, concomitant drugs, immuno-oncology, in vitro modeling
National Category
Pharmacology and Toxicology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-513000 (URN)10.1186/s40360-024-00746-6 (DOI)001179090200002 ()38444002 (PubMedID)
Funder
Swedish Cancer SocietyUppsala University
Available from: 2023-10-02 Created: 2023-10-02 Last updated: 2024-04-04Bibliographically approved
Andersson, C., Ye, J., Blom, K., Fryknäs, M., Larsson, R. & Nygren, P. (2023). Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients. Anti-Cancer Drugs, 34(1), 92-102
Open this publication in new window or tab >>Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients
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2023 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 34, no 1, p. 92-102Article in journal (Refereed) Published
Abstract [en]

Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as 'concomitant drugs', have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2023
Keywords
anti-cancer drug, concomitant medication, combinations, drug interactions
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-493151 (URN)10.1097/CAD.0000000000001344 (DOI)000901618400010 ()36066384 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2023-01-13 Created: 2023-01-13 Last updated: 2023-01-13Bibliographically approved
Cashin, P., Söderström, M., Blom, K., Artursson, S., Andersson, C., Larsson, R. & Nygren, P. (2023). Ex vivo assessment of chemotherapy sensitivity of colorectal cancer peritoneal metastases. British Journal of Surgery, 110(9), 1080-1083
Open this publication in new window or tab >>Ex vivo assessment of chemotherapy sensitivity of colorectal cancer peritoneal metastases
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2023 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 110, no 9, p. 1080-1083Article in journal (Refereed) Published
Abstract [en]

Patients with peritoneal metastasis from colorectal cancer (PMCRC) may have a chance of cure when treated with cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC)1–5.

Choice of chemotherapy for HIPEC has been based on knowledge of its systemic effects, pharmacokinetics, technical feasibility, hyperthermic efficacy enhancement, and tolerance6–8. Selection of cancer drugs for treatment based on phenotypical assessment of patient cancer cell drug sensitivity ex vivo is one approach to personalized cancer treatment. One technique for this is the fluorometric microculture cytotoxicity assay (FMCA) that has been used in drug development and for the development of personalized cancer medicine9–16.

This study investigated whether ex vivo assessment of drug sensitivity by the FMCA provides predictive information in terms of peritoneal recurrence-free survival (PRFS) and overall survival (OS) in patients treated with CRS and HIPEC for isolated PMCRC.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-522422 (URN)10.1093/bjs/znad066 (DOI)000949793400001 ()36918737 (PubMedID)
Available from: 2024-02-12 Created: 2024-02-12 Last updated: 2024-02-12Bibliographically approved
Selvin, T., Berglund, M., Lenhammar, L., Jarvius, M., Nygren, P., Fryknäs, M., . . . Andersson, C. (2023). Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death. BMC Cancer, 23, Article ID 164.
Open this publication in new window or tab >>Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death
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2023 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 23, article id 164Article in journal (Refereed) Published
Abstract [en]

Background: High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents.

Methods: We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death.

Results: The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model.

Conclusion: Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Immuno-oncology, Drug screening, Repurposing, Small molecule drugs, Statins
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-498543 (URN)10.1186/s12885-023-10645-4 (DOI)000935937800002 ()36803614 (PubMedID)
Funder
Swedish Cancer SocietyInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroUppsala University
Available from: 2023-03-22 Created: 2023-03-22 Last updated: 2023-10-02Bibliographically approved
Dijkstra, E. A., Zwart, W. H., Nilsson, P. J., Putter, H., Roodvoets, A. G., Kranenbarg, E.-K. M., . . . Glimelius, B. (2023). The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancerdresults from the RAPIDO trial. ESMO Open, 8(2), Article ID 101158.
Open this publication in new window or tab >>The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancerdresults from the RAPIDO trial
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2023 (English)In: ESMO Open, E-ISSN 2059-7029, Vol. 8, no 2, article id 101158Article in journal (Refereed) Published
Abstract [en]

Background: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial.

Patients and methods: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT >75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression.

Results: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT >75% versus pCT-/-). However, all 95% confidence intervals included 1.

Conclusions: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Place, publisher, year, edition, pages
ELSEVIER, 2023
Keywords
locally advanced rectal cancer, post-operative chemotherapy, oncological outcomes, propensity score stratification, adjuvant chemotherapy
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-506985 (URN)10.1016/j.esmoop.2023.101158 (DOI)001005120500001 ()36871393 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council, K2014-99X-22481-01-3
Available from: 2023-07-03 Created: 2023-07-03 Last updated: 2023-07-03Bibliographically approved
Dahlgren, D., Rosenqvist, E., Hellström, P. M., Nygren, P., Kullenberg, F., Peters, K., . . . Lennernäs, H. (2022). Evaluation and validation of chemotherapy‐specific diarrhoea and histopathology in rats. Basic & Clinical Pharmacology & Toxicology, 131(6), 536-546
Open this publication in new window or tab >>Evaluation and validation of chemotherapy‐specific diarrhoea and histopathology in rats
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2022 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 131, no 6, p. 536-546Article in journal (Refereed) Published
Abstract [en]

Chemotherapy-induced mucositis is characterized by diarrhoea and villous atrophy. However, it is not well-understood why diarrhoea arises, why it only occurs with some chemotherapeutics and how it is related to villus atrophy. The objectives in this study were to determine (i) the relationship between chemotherapy-induced diarrhoea and villus atrophy and to (ii) establish and validate a rat diarrhoea model with clinically relevant endpoints. Male Wistar Han IGS rats were treated with saline, doxorubicin, idarubicin, methotrexate, 5-fluorouracil, irinotecan or 5-fluorouracil+irinotecan. After 72 h, jejunal tissue was taken for morphological, apoptotic and proliferative analyses, and faecal water content and change in body weight were determined. All treatments except methotrexate caused a similar reduction (≈42%) in villus height, but none of them altered mucosal crypt cell proliferation or apoptosis. Doxorubicin, idarubicin, irinotecan and 5-fluorouracil+irinotecan caused body weight reduction, but only irinotecan and idarubicin caused diarrhoea. No direct correlation between diarrhoea and villus height or body weight loss was observed. Therefore, studies of the mechanisms for chemotherapy-induced diarrhoea should focus on functional factors. Finally, the irinotecan and idarubicin diarrhoea models established in this study will be useful in developing supportive treatments of this common and serious adverse effect in patients undergoing chemotherapy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Pharmacology and Toxicology Physiology
Identifiers
urn:nbn:se:uu:diva-486430 (URN)10.1111/bcpt.13790 (DOI)000862175300001 ()36124882 (PubMedID)
Funder
Swedish Cancer Society, CAN2018/602Swedish Research Council, 2020‐02367Swedish Research Council, 2018‐03301
Available from: 2022-10-08 Created: 2022-10-08 Last updated: 2024-05-23Bibliographically approved
Bjersand, K., Blom, K., Sundström Poromaa, I., Stålberg, K., Lejon, A.-M., Bäckman, F., . . . Nygren, P. (2022). Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome. International Journal of Oncology, 61(4), Article ID 128.
Open this publication in new window or tab >>Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome
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2022 (English)In: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 61, no 4, article id 128Article in journal (Refereed) Published
Abstract [en]

Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short-term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross-resistance and association with progression-free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment-naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross-resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.

Place, publisher, year, edition, pages
Spandidos Publications, 2022
Keywords
ovarian cancer, type I and II, drug sensitivity, ex vivo
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-496809 (URN)10.3892/ijo.2022.5418 (DOI)000891722800001 ()36082820 (PubMedID)
Funder
Swedish Cancer Society, 17 0661
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2023-02-22Bibliographically approved
Karlsson, H., Fryknäs, M., Senkowski, W., Larsson, R. & Nygren, P. (2022). Selective radiosensitization by nitazoxanide of quiescent clonogenic colon cancer tumour cells. Oncology Letters, 23(4), Article ID 123.
Open this publication in new window or tab >>Selective radiosensitization by nitazoxanide of quiescent clonogenic colon cancer tumour cells
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2022 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 23, no 4, article id 123Article in journal (Refereed) Published
Abstract [en]

Nitazoxanide is a Food and Drug Administration-approved antiprotozoal drug recently demonstrated to be selectively active against quiescent and glucose-deprived tumour cells. This drug also has several characteristics that suggest its potential as a radiosensitizer. The present study aimed to investigate the interaction between nitazoxanide and radiation on human colon cancer cells cultured as monolayers, and to mimic key features of solid tumours in patients, as spheroids, as well as in xenografts in mice. In the present study, colon cancer HCT116 green fluorescent protein (GFP) cells were exposed to nitazoxanide, radiation or their combination. Cell survival was analysed by using total cell kill and clonogenic assays. DNA double-strand breaks were evaluated in the spheroid experiments, and HCT116 GFP cell xenograft tumours in mice were used to investigate the effect of nitazoxanide and radiation in vivo. In the clonogenic assay, nitazoxanide synergistically and selectively sensitized cells grown as spheroids to radiation. However, this was not observed in cells cultured as monolayers, as demonstrated in the total cell kill assays, and much less with the clinically established sensitizer 5-fluorouracil. The sensitizing effect from nitazoxanide was confirmed via spheroid gamma-H2A histone family member X staining. Nitazoxanide and radiation alone similarly inhibited the growth of HCT116 GFP cell xenograft tumours in mice with no evidence of synergistic interaction. In conclusion, nitazoxanide selectively targeted quiescent glucose-deprived tumour cells and sensitized these cells to radiation in vitro. Nitazoxanide also inhibited tumour growth in vivo. Thus, nitazoxanide is a candidate for repurposing into an anticancer drug, including its use as a radiosensitizer.

Place, publisher, year, edition, pages
Spandidos Publications, 2022
Keywords
nitazoxanide, spheroid, 3D, radiosensitizer, clonogenic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-469559 (URN)10.3892/ol.2022.13243 (DOI)000761364600001 ()35261637 (PubMedID)
Funder
Swedish Cancer Society, 462430020Swedish Foundation for Strategic Research , 2008-03000
Available from: 2022-03-14 Created: 2022-03-14 Last updated: 2022-03-14Bibliographically approved
Nyberg, F., Blom, K., Selvin, T., Rudfeldt, J., Andersson, C., Senkowski, W., . . . Fryknäs, M. (2022). Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma. Scientific Reports, 12, Article ID 8943.
Open this publication in new window or tab >>Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 8943Article in journal (Refereed) Published
Abstract [en]

Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-476608 (URN)10.1038/s41598-022-12519-4 (DOI)000800769400038 ()35624293 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2022-06-27 Created: 2022-06-27 Last updated: 2024-01-15Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0075-127x

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