Beyond the Paclitaxel and Vinca Alkaloids: Next Generation of Plant-Derived Microtubule-Targeting Agents with Potential Anticancer Activity
Abstract
:1. Introduction
2. Microtubule Stabilizing Agents
2.1. Taccalonolides
2.1.1. Mechanism of Action
2.1.2. Tubulin Binding Sites
2.1.3. Structure-Activity Relationships
(A) | |||||||||||||||||||||||||||||||||||||||||||||
Compound | IC50 (μM) | Compound | IC50 (μM) | Compound | IC50 (μM) | Compound | IC50 (μM) | Compound | IC50 | Compound | IC50 (μM) | References: [24,26,30,31,32] | |||||||||||||||||||||||||||||||||
Taccalonolide A | 5.32 ± 0.23 | Taccalonolide N | 8.5 ± 0.40 | Taccalonolide Z | 0.12 ± 0.008 | Taccalonolide AD | 3.4 ± 0.2 | Taccalonolide AO | >50 | Taccalonolide AN | 1.5 ± 0.1 | ||||||||||||||||||||||||||||||||||
Taccalonolide B | 3.12 ± 0.18 | Taccalonolide I | 49.2 ± 2.8 | Taccalonolide AA | 0.032 ± 0.002 | Taccalonolide AE | 5.0 ± 0.2 | Taccalonolide AK | >50 | Paclitaxel | 0.0012 ± 0.1 | ||||||||||||||||||||||||||||||||||
Taccalonolide E | 39.5 ± 4.70 | Taccalonolide R | 13.0 ± 1.0 | Taccalonolide AB | 2.7 ± 0.1 | Taccalonolide AF | 0.023 ± 0.003 | Taccalonolide AL | 34.4 ± 7.5 | ||||||||||||||||||||||||||||||||||||
Taccalonolide H2 | 0.73 ± 0.02 | Taccalonolide T | 0.34 ± 0.02 | Taccalonolide AC | >50 | Taccalonolide AJ | 0.0042 ± 0.0003 | Taccalonolide AM | 2.0 ± 0.1 | ||||||||||||||||||||||||||||||||||||
(B) | |||||||||||||||||||||||||||||||||||||||||||||
Compound | Xenograft Models | Method of Tumor Cell Administration | Treatment Strategy/Dose | References | |||||||||||||||||||||||||||||||||||||||||
Taccalonolide AF and AJ | MDA-MB-231 breast cancer | intraperitoneal | 1. Taccalonolide AF: 2 mg/kg on Days 1, 4, 8 2. Taccalonolide AF: 2.5 mg/kg on Days 1 and 5 3. Taccalonolide AJ: 0.5 mg/kg on Days 1, 3, 5, and 8 | [27] | |||||||||||||||||||||||||||||||||||||||||
Taccalonolide AF and AJ | SCC-4 oral cancer cells | subcutaneous | 1. Taccalonolide AF: 80 μg on Days 0 and 3 2. Taccalonolide AJ: 40 μg on Days 0 and 3 3. Taccalonolide AJ: 80 μg on Days 0 and 3 | [34] | |||||||||||||||||||||||||||||||||||||||||
(C) | |||||||||||||||||||||||||||||||||||||||||||||
Breast Cancer Cell Lines | Ovarian Cancer Cell Lines | Prostate Cancer Cell Lines | Leukemia Cell Lines | References: [35,36,37] | |||||||||||||||||||||||||||||||||||||||||
Compound (μM) | MCF-7 | T-47D | MDA-MB-468 | MDA-MB-157 | SK-BR3 | Hs578T | MDA-MB-231 | MCF-10A | OVCAR-3 | IGROV-1 | 1A9 | A2780 | PC-3 | LNCaP | HL-60 | ||||||||||||||||||||||||||||||
Persin | 15.1 ± 1.3 | 30.3 ± 2.3 | 25.0 ± 2.8 | 12.8 ± 1.2 | 19.7 ± 1.3 | 32.1 ± 2.3 | >39 | >39 | 27.9 ± 4.5 | 15.6 ± 3.6 | 13.7 ± 0.6 | 8.1 ± 1.1 | 30.0 ± 3.0 | 22.0 ± 1.8 | 1.9 ± 0.1 | ||||||||||||||||||||||||||||||
1 | 17.1 ± 1.7 | 20.7 ± 3.2 | >39 | >39 | >39 | >39 | >39 | >39 | >39 | >39 | 4.1 ± 0.4 | 8.1 ± 1.4 | >39 | >39 | 0.6 ± 0.03 | ||||||||||||||||||||||||||||||
2 | >32 | 18.9 ± 1.3 | 13.7 ± 0.9 | 4.0 ± 0.1 | |||||||||||||||||||||||||||||||||||||||||
3 | 27.7 ± 5.5 | 19.4 ± 2.2 | 2.6 ± 0.4 | ||||||||||||||||||||||||||||||||||||||||||
4 | >27 | 21.2 ± 1.8 | 7.5 ± 0.2 | ||||||||||||||||||||||||||||||||||||||||||
5 | 23.8 ± 2.2 | 34.1 ± 5.3 | 5.8 ± 0.1 | ||||||||||||||||||||||||||||||||||||||||||
6 | 29.0 ± 4.2 | 47.6 ± 3.5 | 28.4 ± 0.5 | ||||||||||||||||||||||||||||||||||||||||||
7 | >21 | ||||||||||||||||||||||||||||||||||||||||||||
8 | >24 | ||||||||||||||||||||||||||||||||||||||||||||
9 | 20.1 ± 3.6 | ||||||||||||||||||||||||||||||||||||||||||||
10 | >65 | 124 ± 20 | 22.8 ± 1.0 | ||||||||||||||||||||||||||||||||||||||||||
(D) | |||||||||||||||||||||||||||||||||||||||||||||
Breast Cancer Cell Lines | Lung Cancer Cell Lines | Squamous Carcinoma Cell Lines | Lymphoma Cell Lines | Ovarian Cancer Cell Line | Cervical Cancer Cell Line | Leukemia Cell Line | Prostate Cancer Cell Line | References | |||||||||||||||||||||||||||||||||||||
Compound | MCF7 | MDA-MB-231 | BT-474 | SK-BR3 | MDA-MB-435 | A594 | H1299 | H292 | NCI-H358M | Tu212 | Tu686 | BJAB | OVCAR-8 | HeLa | HL60 | LNCap | PC3M | ||||||||||||||||||||||||||||
Curcumin (μM) | 11.2 | 6.03 | 11.6 | 5.5 | 6.4 | 25.0 | [38,39,40,41,42] | ||||||||||||||||||||||||||||||||||||||
Maytansine (pM) | 30 | 420 | 44 | 270 | [43,44,45] | ||||||||||||||||||||||||||||||||||||||||
Combretastatin A4 (nM) | 2.8 | 5.3 | 3.8 | 8 | 0.37 | 0.9 | 2.1 | 4.7 | [46,47] | ||||||||||||||||||||||||||||||||||||
Noscapine (μM) | 29 | 69 | [48] | ||||||||||||||||||||||||||||||||||||||||||
Quercetin (μM) | 14 | 1 | 22 | [49] |
2.1.4. Advantages over Paclitaxel
2.2. Persin
2.2.1. Mechanism of Action
2.2.2. Tubulin Binding Sites
2.2.3. Structure-Activity Relationships
2.2.4. Persin Activity in MTA-Resistant Cells
3. Microtubule Destabilizing Agents
3.1. Curcumin
3.1.1. Mechanism of Action
3.1.2. Tubulin Binding Sites
3.1.3. Structure-Activity Relationships
3.2. Combretastatins
3.2.1. Mechanism of Action and the Tubulin Binding Sites
3.2.2. Structure–Activity Relationships
3.3. Noscapine
3.3.1. Mechanism of Action
3.3.2. Tubulin Binding Sites
3.3.3. Structure–Activity Relationships
3.4. Maytansinoids
3.4.1. Mechanism of Action and the Tubulin Binding Sites
3.4.2. Structure–Activity Relationships
3.5. Chalcones and Quercetin
Mechanism of Action and Tubulin Binding Sites
4. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | Stage of Development | Clinical Trial | ||
---|---|---|---|---|
Active (NCI clinical trial identifier, Study phase, Year of study start) | Completed (NCI clinical trial identifier, Study phase, Year of study start–study completed) | Withdrawn/Terminated/Suspended (NCI clinical trial identifier, Study phase, Year of study start–study withdrawn/terminated/suspended) | ||
Taccalonolide | Pre-clinical (in vitro cell-based studies and in vivo human tumor xenograft studies in mice) | - | - | - |
Persin | Pre-clinical (in vitro cell-based studies) | - | - | - |
Curcumin | Clinical (Total 60 clinical trials: 22 active, 26 completed, and 12 withdrawn/terminated/suspended trials) | NCT04403568, Early Phase 1, 2020 NCT02724202, Early Phase 1, 2016 NCT03980509, Phase 1, 2020 NCT01859858, Phase 1, 2013 NCT01294072, Phase 1, 2011 NCT02598726, Phase 1, 2016 NCT02336087, Phase 1, 2016 NCT04294836, Phase 2, 2020 NCT00745134, Phase 2, 2020 NCT02724618, Phase 2, 2016 NCT04266275, Phase 2, 2020 NCT00745134, Phase 2, 2008 NCT03192059, Phase 2, 2017 NCT03598309, Phase 2, 2019 NCT02782949, Phase 2, 2017 NCT03493997, Phase 2, 2017 NCT03769766, Phase 3, 2019 NCT02064673, Phase 3, 2014 NCT03847623, Phase N/A, 2017 NCT03865992, Phase N/A, 2019 NCT01948661, Phase N/A, 2014 NCT03431896, Phase N/A, 2018 | NCT01160302, Early Phase 1, 2010–2016 NCT01035580, Phase 1, 2010–2012 NCT01333917, Phase 1, 2010–2013 NCT00027495, Phase 1, 2001–2007 NCT01201694, Phase 1, 2011–2014 NCT01042938, Phase 2, 2008–2011 NCT02439385, Phase 2, 2015–2019 NCT03072992, Phase 2, 2017–2019 NCT01490996, Phase 1/2. 2012–2017 NCT00192842, Phase 2, 2004–2010 NCT01740323, Phase 2, 2015–2018 NCT00094445, Phase 2, 2004–2014 NCT02556632, Phase 2, 2015–2016 NCT02017353, Phase 2, 2013–2016 NCT00641147, Phase 2, 2010–2016 NCT00365209, Phase 2, 2006–2011 NCT02100423, Phase 2, 2014–2018 NCT01246973, Phase 2/3, 2011–2015 NCT01712542, Phase N/A, 2012–2013 NCT03290417, Phase N/A, 2017–2019 NCT01975363, Phase N/A, 2013–2016 NCT01917890, Phase N/A, 2011–2013 NCT03211104, Phase N/A, 2007–2015 NCT00113841, Phase N/A, 2004–2009 NCT03482401, Phase N/A, 2017–2019 NCT00927485, Phase N/A, 2007–2016 | NCT01608139, Phase 1, 2012 NCT00247026, Phase 1/2, 2007 NCT02300727, Phase 1/2, 2015–2018 NCT02095717, Phase 2, 2014–2018 NCT00852332, Phase 2, 2009–2017 NCT02944578, Phase 2, 2017 NCT01269203, Phase 2, 2012 NCT00248053, Phase 2, 2005 NCT00969085, Phase 2, 2012 NCT00003365, Phase N/A, 1996–2006 NCT00118989, Phase N/A, 2005–2012 NCT00176618, Phase N/A, 2004–2007 |
Combretastatin | Clinical (Total 17 clinical trials: 1 active, 11 completed, and 5 withdrawn/terminated/suspended trials) | NCT02576301, Phase 1/2, 2015 | NCT00395434, Phase 1, 2006–2007 NCT00960557, Phase 1, 2009–2010 NCT00003698, Phase 1, 1998–2003 NCT00003768, Phase 1, 1998–2001 NCT01240590, Phase 1/2, 2011–2016 NCT00653939, Phase 2, 2008–2011 NCT00060242, Phase 2, 2003–2008 NCT00113438, Phase 2, 2005–2007 NCT02132468, Phase 2, 2014–2016 NCT02279602, Phase 2, 2014–2016 NCT00699517, Phase 3, 2008–2013 | NCT01085656, Phase 1, 2011–2016 NCT00077103, Phase 1/2, 2003–2007 NCT00507429, Phase 2/3, 2007–2011 NCT02641639, Phase 2/3, 2016–2017 NCT01701349, Phase 3, 2015–2017 |
Noscapine | Clinical (Total 2 clinical trials: 2 terminated trials) | NCT00912899, Phase 1, 2007–2010 NCT00183950, Phase 1/2, 2000–2006 | ||
Maytansinoids as ADC | Clinical (Total 92 clinical trials: 42 active, 37 completed, 13 withdrawn/terminated/suspended trials) | NCT04189211, Phase 1, 2017 NCT03364348, Phase 1, 2017 NCT03102320, Phase 1, 2017 NCT04042051, Phase 1, 2019 NCT03552471, Phase 1, 2018 NCT02996825, Phase 1, 2017 NCT04296942, Phase 1, 2020 NCT02390427, Phase 1, 2015 NCT03126630, Phase 1/2, 2018 NCT04298918, Phase 1/2, 2020 NCT03816358, Phase 1/2, 2019 NCT01565200, Phase 2, 2012 NCT03832361, Phase 2, 2020 NCT03418558, Phase 2, 2015 NCT02675829, Phase 2, 2016 NCT01494662, Phase 2, 2012 NCT01904903, Phase 2, 2013 NCT01853748, Phase 2, 2013 NCT04351230, Phase 2, 2020 NCT02452554, Phase 2, 2015 NCT03225937, Phase 2, 2012 NCT04419181, Phase 2, 2020 NCT03894007, Phase 2, 2019 NCT00781612, Phase 2, 2008 NCT04341181, Phase 2, 2020 NCT02314481, Phase 2, 2017 NCT04197687, Phase 2, 2020 NCT04266249, Phase 2, 2020 NCT04274426, Phase 2, 2020 NCT03587311, Phase 2, 2018 NCT02465060, Phase 2, 2015 NCT03784599, Phase 2, 2018 NCT03726879, Phase 3, 2019 NCT01966471, Phase 3, 2014 NCT04296890, Phase 3, 2020 NCT01702571, Phase 3, 2012 NCT01772472, Phase 3, 2013 NCT03084939, Phase 3, 2017 NCT03529110, Phase 3, 2018 NCT04209855, Phase 3, 2019 NCT04185649, Phase 3, 2018 NCT02226276, Phase N/A, 2015 | NCT03153163, Phase 1, 2017–2018 NCT02696642, Phase 1. 2016–2019 NCT01439152, Phase 1, 2011–2019 NCT01513083, Phase 1, 2012–2014 NCT02824042, Phase 1, 2016–2019 NCT02751918, Phase 1, 2016–2019 NCT02254018, Phase 1, 2002–2014 NCT02038010, Phase 1, 2014–2017 NCT01816035, Phase 1, 2014–2017 NCT02605915, Phase 1, 2015–2019 NCT00934856, Phase 1/2, 2009–2013 NCT00875979, Phase 1/2, 2009–2011 NCT00951665, Phase 1/2, 2009–2013 NCT01638936, Phase 1/2, 2012–2018 NCT01001442, Phase 1/2, 2010–2016 NCT01470456, Phase 2, 2011–2014 NCT01472887, Phase 2, 2012–2016 NCT0261014, Phase 2, 2015–2019 NCT03023722, Phase 2, 2017–2019 NCT02924883, Phase 2, 2016–2020 NCT02289833, Phase 2, 2014–2018 NCT03106077, Phase 2, 2017–2019 NCT01975142, Phase 2, 2013–2019 NCT02254005, Phase 2, 2002–2014 NCT00679211, Phase 2, 2008–2011 NCT00509769, Phase 2, 2007–2009 NCT01196052, Phase 2, 2010–2013 NCT02999672, Phase 2, 2016–2018 NCT00679341, Phase 2, 2008–2012 NCT00943670, Phase 2, 2009–2011 NCT02420873, Phase 2, 2015–2017 NCT00829166, Phase 3, 2009–2015 NCT02631876, Phase 3, 2016–2020 NCT0112018, Phase 3, 2010–2016 NCT01419197, Phase 3, 2011–2015 NCT02131064, Phase 3, 2014–2018 NCT02658734, Phase 4, 2016–2019 | NCT02221505, Phase 1, 2014–2015 NCT03045393, Phase 1, 2017–2018 NCT03455556, Phase 1, 2018–2020 NCT02947152, Phase 1, 2016–2017 NCT02318901, Phase 1/2, 2014–2018 NCT02658084, Phase 1/2, 2017–2018 NCT03836157, Phase 2, 2019 NCT02725541, Phase 2, 2016–2019 NCT02839681, Phase 2, 2016–2018 NCT01702558, Phase 2, 2012–2017 NCT01440179, Phase 2, 2011–2014 NCT01641939, Phase 2/3, 2012–2016 NCT02144012, Phase 3, 2014–2016 |
Chalcones | Pre-clinical (in vitro cell-based studies) | - | - | - |
Quercetin | Clinical (Total 10 clinical trials: 7 active, 1 completed, and 2 withdrawn/terminated trials | NCT01912820, Phase 1, 2014 NCT03493997, Phase 2, 2017 NCT01961869, Phase 2, 2013 NCT03476330, Phase 2, 2018 NCT04252625, Phase 2, 2020 NCT02195232, Phase 2/3, 2015 NCT04267874, Phase N/A, 2019 | NCT01732393, Phase 1/2, 2010–2012 | NCT02989129, Early Phase 1, 2018–2020 NCT00003365, Phase N/A, 1996–2006 |
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Zhang, D.; Kanakkanthara, A. Beyond the Paclitaxel and Vinca Alkaloids: Next Generation of Plant-Derived Microtubule-Targeting Agents with Potential Anticancer Activity. Cancers 2020, 12, 1721. https://doi.org/10.3390/cancers12071721
Zhang D, Kanakkanthara A. Beyond the Paclitaxel and Vinca Alkaloids: Next Generation of Plant-Derived Microtubule-Targeting Agents with Potential Anticancer Activity. Cancers. 2020; 12(7):1721. https://doi.org/10.3390/cancers12071721
Chicago/Turabian StyleZhang, Dangquan, and Arun Kanakkanthara. 2020. "Beyond the Paclitaxel and Vinca Alkaloids: Next Generation of Plant-Derived Microtubule-Targeting Agents with Potential Anticancer Activity" Cancers 12, no. 7: 1721. https://doi.org/10.3390/cancers12071721